Objective To compare the serum glycerophospholipid levels in the inflammatory subtypes of asthma by using targeted metabolomic analysis. Methods Demographic and clinical data were collected from 51 patients with asthm...Objective To compare the serum glycerophospholipid levels in the inflammatory subtypes of asthma by using targeted metabolomic analysis. Methods Demographic and clinical data were collected from 51 patients with asthma between January 2015 and December 2015. Routine blood and sputum induction tests were performed. Eosinophilic asthma was defined as induced sputum containing ≥ 3% eosinophils, and neutrophilic asthma, as induced sputum containing ≥ 71% neutrophils. Serum metabolic glycerophospholipid profile was determined by liquid chromatography-mass spectrometry. Differences in glycerophospholipid levels between eosinophilic and non-eosinophilic asthma and between neutrophilic and non-neutrophilic asthma were analyzed using partial least squares discriminant analysis. Results The serum lysophosphatidylglycerol level was significantly higher in the group with ≥ 3% eosinophils in sputum than in the group with < 3% eosinophils in sputum. The area under the receiver-operating characteristic curve was ≥ 70%. There was no significant difference in the serum metabolic glycerophospholipid profile between the group with sputum neutrophils ≥ 71% and the group with sputum neutrophils < 71%. Conclusion Serum lysophosphatidylglycerol is produced abundantly in eosinophilic asthma and may be a biomarker of eosinophilic asthma. This information is helpful for identifying and tailoring treatment for the common asthma subtypes.展开更多
AIM: To investigate the levels of serum soluble intercellular adhesion molecules-1 (sICAM-1) and neutrophilic expression of CD18 in patients with various stages of diabetic retinopathy and to determine their different...AIM: To investigate the levels of serum soluble intercellular adhesion molecules-1 (sICAM-1) and neutrophilic expression of CD18 in patients with various stages of diabetic retinopathy and to determine their different expression pattern in the development of diabetic retinopathy(DR). METHODS: Levels of serum sICAM-1 and CD18 on the surface of neutrophile were measured in 41 DR patients, they were classified in three subgroups according to the stage of retinopathy as determined by fund's ophthalmoscopy; 10 control subjects were also studied. sICAM-1 were measured by enzyme-linked immunosorbent assay and CD18 by flow cytometry. RESULTS: The neutrophilic CD18 expression and serum sICAM-1 level were all significantly elevated in all diabetic subgroups compared to control subjects (P <0.01). The differences of CD18 and sICAM-1 among the diabetic subgroups were significant in CD18 but not in sICAM-1. The progression of retinopathy was associated with an increase both in CD18 and in sICAM-1 levels by simple correlation analysis (beta =0.74, P<0.001; beta =0.38, P<0.01, respectively). But stepwise multiple regression analysis revealed that only CD18 Was independent determinant of retinopathy (beta =1.04, P<0.01). CONCLUSION: Our results confirm the contribution of endothelial and neutrophilic activation in the development of DR as indicated by increased levels of CD18 and sICAM-1. However, a direct implication of CD18 and ICAM-1 in the progression of DR can be supported only in the CD18 but not ICAM-1. CD18 and ICAM-1 may play different role in the development of diabetic retinopathy.展开更多
OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
BACKGROUNDChronic neutrophilic leukemia (CNL) is a rare bone marrow proliferative tumorand a heterogeneous disorder. In 2016, the World Health Organization includedactivating mutations in the CSF3R gene as one of the ...BACKGROUNDChronic neutrophilic leukemia (CNL) is a rare bone marrow proliferative tumorand a heterogeneous disorder. In 2016, the World Health Organization includedactivating mutations in the CSF3R gene as one of the diagnostic criteria, withCSF3R T618I being the most common mutation. The disease is often accompaniedby splenomegaly, but no developmental abnormalities and significant reticularfibrosis, and no Ph chromosome and BCR-ABL fusion gene. So, it is difficult todiagnose at the first presentation in the absence of classical symptoms. Herein wedescribe a rare CNL patient without splenomegaly whose initial diagnostic cluewas neutrophilic hyperactivity.CASE SUMMARYThe patient is an 80-year-old Han Chinese man who presented with one month offatigue and fatigue aggravation in the last half of the month. He had nosplenomegaly, but had persistent hypofibrinogenemia, obvious skin bleeding, andhemoptysis, and required repeated infusion of fibrinogen therapy. After manyrelevant laboratory examinations, histopathological examination, and sequencinganalysis, the patient was finally diagnosed with CNL [CSF3R T618I positive:c.1853C>T (p.T618I) and c.2514T>A (p.C838)].CONCLUSIONThe physical examination and blood test for tumor-related genes are insufficientto establish a diagnosis of CNL. Splenomegaly is not that important, buthyperplasia of interstitial neutrophil system and activating mutations in CSF3Rare important clues to CNL diagnosis.展开更多
Purpose of the study: Research of the clinical and diagnostic significance of determination of Lipocalin-2 associated with neutrophilic gelatinases (uNGAL) in the urine of children with urinary tract infection (UTI) a...Purpose of the study: Research of the clinical and diagnostic significance of determination of Lipocalin-2 associated with neutrophilic gelatinases (uNGAL) in the urine of children with urinary tract infection (UTI) and pyelonephritis. Materials and methods: We examined 30 children with acute pyelonephritis and UTI aged 1 to 16 years (average age 7.32 ± 4.52) including 26 girls and 4 boys. Verification of the diagnosis was conducted on the basis of clinical and laboratory data, medical history and instrumental examination of patients. All children were divided into 2 groups: 1st group—15 children with acute pyelonephritis, 2nd group—15 children with urinary tract infection. uNGAL was measured in the urine by enzyme-linked immunosorbent assay (EISA) (BioVendor Laboratoty Medicine). Results: It is found, that the urine level of NGAL depends on the damage degree of renal parenchyma. The correlation of medium strength was found between the excretion level of uNGAL during the acute period of pyelonephritis and the detection of renal scars according to the DMSA-nephroscintigraphy data. In the group of children with the acute pyelonephritis the direct correlation of medium strength was found between the excretion level of uNGAL/creatinine and leukocytosis value and also with the CRP blood level. Conclusion: The results allow us to recommend the determination of the excretion level of uNGAL/creatinine as an additional non-invasive marker for the early detection of renal parenchyma injury.展开更多
Objective:By comparing the efficacy of different frequency application of polyethylene glycol recombinant human granulocyte stimulating factor in the prevention of neutropenia after chemotherapy with dose-intensive re...Objective:By comparing the efficacy of different frequency application of polyethylene glycol recombinant human granulocyte stimulating factor in the prevention of neutropenia after chemotherapy with dose-intensive regimen in breast cancer, the more optimized administration scheme of polyethylene glycol recombinant human granulocyte stimulating factor in the prevention of neutropenia after chemotherapy in breast cancer was further explored.Methods:From June 2017 to May 2019, 64 patients with breast cancer who had received dose-intensive chemotherapy from June 2017 to May 2019 were randomly divided into two groups: control group (n=31) and observation group (n=33). Control group: after dose-intensive chemotherapy, PEG-rhG-CSF was injected subcutaneously with 100μg/kg, and given 24 hours after chemotherapy. Observation group: after dose-intensive chemotherapy, PEG-rhG-CSF: 50μg/kg, was injected subcutaneously and given 24 hours and 72 hours after chemotherapy. With PEG-rhG-CSF on the number of neutrophils in the two groups and the incidence, duration, fever incidence and duration of neutropenia in the two groups were observed. The curative effect was evaluated after 2 cycles of treatment.Results: There was no significant difference in the number of neutrophils between the two groups before chemotherapy in the first cycle and the second cycle (P>0.05), but the neutrophils in the observation group decreased slowly on the 3rd day, 5th day, 10th day and 5th day and 10th day after the first cycle of chemotherapy, and there was significant difference between the two groups (P<0.001). In the second cycle, there was no significant difference in neutrophils between the two groups on the third day after chemotherapy (P<0.05). In the control group, 7 patients were delayed by the second week because the neutrophil value was less than 2.0109/ L. The time of chemotherapy was delayed in 5 patients in the observation group. The incidence of neutropenia in the control group and the observation group was 41.9% VS 12.1%, and the duration of neutropenia in the observation group was significantly shorter than that in the control group (3.25 ±0.84d VS 5.12 ±1.24d), and the incidence of neutropenia in the observation group was 41.9% VS 12.1%, the duration of neutropenia in the observation group was significantly shorter than that in the control group (3.25 ±0.84d VS 5.12 ±1.24d). The number of patients with fever in the control group and the observation group were 10 cases of VS, the incidence rate was 32.2% VS 12.1%, compared with the control group and the observation group, the incidence of febrile fever was 32.2% and 12.1%, respectively. The duration of fever in the observation group was significantly shorter than that in the control group (2.46 ±1.24 d VS 4.05 ±1.01).Conclusions: Low dose of PEG-rhG-CSF can increase the absolute value of neutrophils after multiple administration, and its curative effect is better than that of single administration in dose-intensive chemotherapy, and the incidence of neutropenia and associated fever is lower, which is worthy of further clinical study and promotion.展开更多
Aim. To elucidate whether an inhibited superoxide production(O 2 ) of neutrophils induced by commercial lactate based peritoneal dialysates(PDS) could be corrected after a transient intracel...Aim. To elucidate whether an inhibited superoxide production(O 2 ) of neutrophils induced by commercial lactate based peritoneal dialysates(PDS) could be corrected after a transient intracellular acidosis. Methods. The intracellular pH([pHi]) of human neutrophils incubatd in PDS was monitored with a spectrofluorometer with a pH sensitive dye (BCECF AM). Neutrophilic O 2 stimulated by zymosan was determined in PDS with the superoxide dismutase inhibitable ferricytochrome c reduction, using a spectrophotometer. Results. The severe intracellular acidosis induced within 5 min by PDS at an extracellular pH of 5.2 could be promptly and completely recovered by a neutralization of the pH of media. However, O 2 by neutrophils exposed to the PDS for as little as 5 min was drastically and persistently inhibited, even the acidic [pHi] of cells had been fully returned for 1h. Conclusions. The intracellular acidification of cells in the initial phase could be transient and reversible, but impaired cell functions, at least in part including O 2 generating system, might be consistent and irreversible in the early stage of the cellular acidosis in the peritoneal cavity of CAPD patients. The findings above may be of particular importance in both clinic and cell biology.展开更多
Metabolic dysfunction-associated steatohepatitis(MASH)is the progressive form of metabolic dysfunction-associated steatotic liver disease(MASLD),and closely associated with a high risk of liver-related morbidity and m...Metabolic dysfunction-associated steatohepatitis(MASH)is the progressive form of metabolic dysfunction-associated steatotic liver disease(MASLD),and closely associated with a high risk of liver-related morbidity and mortality.Although enhanced neutrophil infiltration of the liver is a histological hallmark of MASH,the morphological pattern of hepatic neutrophils and their relevance to the definition of MASH remain unknown.This clinicopathological study aimed to determine the association of neutrophilic crown-like structures(CLSs)in liver biopsies and evaluate their relevance to the histological diagnosis of MASH.A total of 483 morbidly obese adults who underwent bariatric surgery were recruited.Neutrophilic CLSs in liver biopsies were detected by immunohistochemistry for neutrophil elastase and proteinase 3.All participants were classified into 4 histological subgroups:no MASLD(118,24.4%),MASLD(76,15.7%),borderline MASH(185,38.3%),and definite MASH(104,21.5%).In the discovery cohort(n=379),the frequency of neutrophilic CLSs increased in line with the severity of liver disease.The number of neutrophilic CLSs was positively correlated with established histological characteristics of MASH.At a cutoff value of<0.3 per 20×microscopic field,the number of neutrophilic CLSs yielded a robust diagnostic accuracy to discriminate no MASLD and MASLD from borderline MASH and definite MASH;a cutoff at>1.3 per 20×microscopic field exhibited a statistically significant accuracy to distinguish definite MASH from other groups(no MASLD,MASLD,and borderline MASH).The significance of neutrophilic CLSs in identifying borderline MASH and definite MASH was confirmed in an external validation cohort(n=104).The frequency of neutrophilic CLSs was significantly higher than that of macrophagic CLSs.In conclusion,neutrophilic CLSs in the liver represent a typical histological characteristic of MASH and may serve as a promising indicator to improve the diagnostic accuracy of MASH during histological assessment of liver biopsies.展开更多
Psoriasis and other inflammatory skin diseases remain challenging to manage,in part owing to an incomplete understanding of how stromal cells,including fibroblasts and adipocytes,shape the inflammatory milieu.In their...Psoriasis and other inflammatory skin diseases remain challenging to manage,in part owing to an incomplete understanding of how stromal cells,including fibroblasts and adipocytes,shape the inflammatory milieu.In their recent study,Xia et al.revealed an unexpected dual role for dermal adipocyte lineage cells,describing how these cells first promote and later restrain neutrophil-driven inflammation through a dynamic interplay of chemokine production and lipid-mediated resolution[1].展开更多
The immune response of the skin to danger signals involves rapid recruitment of neutrophils,but their excessive accumulation leads to inflammatory skin diseases,such as psoriasis;however,the mechanisms governing their...The immune response of the skin to danger signals involves rapid recruitment of neutrophils,but their excessive accumulation leads to inflammatory skin diseases,such as psoriasis;however,the mechanisms governing their initiation and resolution are poorly understood.Here,we revealed a dynamic immunoregulatory role of dermal white adipose tissue(dWAT)in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model.During inflammation onset,dWAT repopulates PDGFRA+preadipocytes(pAds),which secrete CXCL1 and SAA3,attracting and activating CXCR2+neutrophils.These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway,establishing a self-sustaining inflammatory loop.Paradoxically,prolonged IL-1βsignaling triggers PPARγ-dependent adipogenesis,transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators.Inhibition of adipogenesis,via pharmacological or genetic inhibition of PPARγ,disrupts the formation of early adipocytes,prevents neutrophil regression,and exacerbates inflammation.Analysis of human psoriatic cells revealed a C/EBPδ+dermal fibroblast(dFB)subpopulation enriched with preadipocytes,the IL-1 pathway,and inflammatory gene signatures.Furthermore,transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis.Together,our findings reveal the dual role of dWAT:PDGFRA+pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils,whereas PPARγ-driven adipogenesis resolves this process through lipid mediators.This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases,such as psoriasis and ulcers.展开更多
Introduction:Neutrophilic panniculitis(NP)is a rare subtype of neutrophilic dermatosis,a group of neutrophilrich inflammatory skin disorders that can present in association with myeloid neoplasms.NP is defined by the ...Introduction:Neutrophilic panniculitis(NP)is a rare subtype of neutrophilic dermatosis,a group of neutrophilrich inflammatory skin disorders that can present in association with myeloid neoplasms.NP is defined by the presence of a neutrophilic infiltrate in the fat lobules of the subcutis in the absence of either infection or vasculitis.We herein describe a 65-year-old woman with a recent diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome(MDS/MPN)who abruptly developed painful,pruritic nodules consistent with NP.Case presentation:A 65-year-old woman with MDS/MPN presented for evaluation of painful and pruritic nodules on her upper and lower extremities.A biopsy revealed a lobular neutrophilic infiltrate in the subcutis without evidence of microorganisms or vasculitis.The patient was diagnosed with NP and treated with oral prednisone.Within 1 month of treatment,she reported complete resolution of the nodules.Discussion:Similar to other neutrophilic dermatoses,NP may arise in association with hematologic malignancies of myeloid origin,such as MDS/MPN.A literature review revealed that most cases of NP associated with MDS occur after the onset of MDS and respond to systemic corticosteroids,not antibiotics.Infection should be ruled out before initiating treatment with systemic steroids.Conclusion:Although the mechanism is still unknown,it is important for clinicians to be aware that NP is associated with MDS;thus,hematological malignancies should be investigated on diagnosis of NP.Once diagnosed,NP is easily treated and has an excellent response to systemic corticosteroids.展开更多
Objective:To investigate the effects of ligustrazine(LTZ)on airway inflammation in a mouse model of neutrophilic asthma(NA).Methods:Forty healthy C57 BL/6 female mice were randomly divided into 4 groups using a random...Objective:To investigate the effects of ligustrazine(LTZ)on airway inflammation in a mouse model of neutrophilic asthma(NA).Methods:Forty healthy C57 BL/6 female mice were randomly divided into 4 groups using a random number table,including the normal control,NA,LTZ and dexamethasone(DXM)groups,with 10 rats in each group.The NA mice model was established by the method of ovalbumin combined with lipopolysaccharide sensitization.At 0.5 h before each challenge,LTZ and DXM groups were intraperitoneally injected with LTZ(80 mg/kg)or DXM(0.5 mg/kg)for 14 d,respectively,while the other two groups were given the equal volume of normal saline.After last challenge for 24 h,the aerosol inhalation of methacholine was performed and the airway reactivity was measured.The bronchoalveolar lavage fluid(BALF)was collected.The Wright-Giemsa staining was used for total white blood cells and differential counts.The levels of cytokines interleukin(IL)-17 and IL-10 were detected by enzyme-linked immunosorbent assay.The pathological change of lung tissue was observed by hematoxylin eosin staining.Results:The airway responsiveness of the NA group was significantly higher than the normal control group(P<0.05),while those in the LTZ and DXM groups were significantly lower than the NA group(P<0.05).The neutrophil and eosinophil counts in the LTZ and DXM groups were significantly lower than the NA group(P<0.05),and those in the LTZ group were significantly lower than the DXM group(P<0.05).There were a large number of peribronchiolar and perivascular inflammatory cells in filtration in the NA group.The airway inflammation in the LTZ and DXM groups were significantly alleviated than the NA group.The infiltration in the LTZ group was significantly reduced than the DXM group.Compared with the normal control group,the IL-17 level in BALF was significantly increased and the IL-10 level in BALF was significantly decreased in the NA group(P<0.05).LTZ and DXM treatment significantly decreased IL-17 levels and increased IL-10 levels compared with the NA group(P<0.05),and the changes in the above indices were more significant in the LTZ group(P<0.05).Conclusion:LTZ could alleviate the airway inflammation in the NA mice model through increasing the IL-10 level and decreasing the IL-17 level.展开更多
Objective To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia （CNL）. Data sources Data cited in this review were obtained mainly from Pub...Objective To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia （CNL）. Data sources Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms ＂chronic neutrophilic leukemia＂ and ＂diagnosis＂ were used for the literature search. Study selection We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL. Results The discovery of high-frequency granulocyte-colony stimulating factor receptor （CSF3R） mutations in CNL identifies a new major diagnostic criterion, and lends more specificity to the World Health Organization （WHO） diagnostic criteria for CNL, which are variably applied in routine clinical practice. Conclusions In patients for whom the cause of neutrophilia is not easily discerned, the incorporation of CSF3R mutation testing can be a useful point-of-care diagnostic to evaluate the presence of a clonal myeloid disorder, as well as providing the potential for genetically informed therapy. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of the SRC family-TNK2 and JAK kinases and may provide a new avenue for therapy.展开更多
Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen spec...Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen species,degranulation,and NETosis(formation of neutrophil extracellular traps[NETs]).NETs,which contain antimicrobial compounds such as myeloperoxidase(MPO),represent a strategy to combat infection.However,excessive production of NETs promotes thrombosis,diabetes mellitus,and other diseases.Therefore,investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders.Here,we identified a novel NETosis inducer,human serum albumin(HSA)modified by the MPO product hypochlorous acid(HSAHOCl),whose accumulation in vivo was correlated with inflammatory processes.Using human blood neutrophils,we investigated HSAHOCl-induced NETosis and detected NET formation by flow cytometry.The results showed that the mechanism of HSAHOClinduced NETosis involved MPO,NADPH oxidase,and phosphatidylinositol 3-kinases(PI3Ks),and that HSAHOCl activated a reactive oxygen species-dependent suicidal type of NETosis.Moreover,HSAHOCl-induced NETosis was inhibited by an anti-HSAHOCl monoclonal antibody.Thus,our findings may facilitate the development of strategies to modulate NETosis in inflammation associated with elevated MPO activity.展开更多
Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microb...Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microbial inflammatory disease,the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown.Here,we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology,cha racterized by poorer respiratory function,thicke ned bronchial walls,and increased neutrophils infiltration in lung tissue.Mechanistically,periodontitis pathogen Porphyromonas gingivalis(P.gingivalis)relocated in the lung through the respiratory tract and LPS from P.gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils.Furthermore,exposure to P.gingivalis of infiltrated neutrophils released matrix metallopeptidase-8(MMP-8)and neutrophil elastase(NE),which aggravated airway inflammation and tissue damage.These findings indicated that periodontitis could exacerbate COPD via its pathogen P.gingivalis,which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.展开更多
Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the mole...Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.展开更多
Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for patho...Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for pathogen clearance,aberrant NETosis has emerged as a critical modulator of acute and chronic respiratory pathologies,including acute respiratory distress syndrome,asthma,and chronic obstructive pulmonary disease.Dysregulated NET release exacerbates airway inflammation by inducing epithelial injury,mucus hypersecretion,and the recruitment of inflammatory leukocytes,thereby accelerating tissue remodeling and functional decline.Mechanistically,NETosis is governed by peptidyl arginine deiminase 4(PADI4)-mediated histone citrullination,NADPH oxidase-dependent reactive oxygen species production,mitochondrial metabolic reprogramming,and activation of toll-like receptors and inflammasomes.These molecular events perpetuate inflammation and prevent its resolution.Emerging evidence indicates that natural bioactive compounds,such as flavonoids,terpenoids,and polyphenols,attenuate NETosis by modulating oxidative stress,inhibiting PADI4 activation,or suppressing downstream pro-inflammatory cascades.Collectively,these findings highlight the therapeutic potential of targetingNETosis tomitigate neutrophil-driven airway pathology.This review aims to comprehensively synthesize recent mechanistic insights into NETosis and to delineate how modulation of NET formation contributes to the prevention and treatment of inflammatory respiratory diseases.展开更多
Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that ...Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing.A unique Il4ra^(+)Ccl2^(high) neutrophil subset drove intense postinjury TRPV1^(+)nociceptive ingrowth,which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4(LXA4)in osteoblasts.Mechanistically,osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide(CGRP)suppressed the nuclear translocation of arachidonate 5-lipoxygenase(5-LOX)to favor the LXA4 biosynthesis.Moreover,in alveolar bone from patients with Type Ⅱ diabetes,we found diminished nociceptive innervation correlated with reduced autophagy,increased inflammation,and impaired bone formation.Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice.These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.展开更多
Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function...Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.展开更多
基金funded by the National Natural Science Foundation of China Youth Fund Project [No.81400017]the National Natural Science Foundation of China Emergency Management Project [No.81641153]the Returned Overseas Chinese Scholars Startup Fund [No.Y81484-02]
文摘Objective To compare the serum glycerophospholipid levels in the inflammatory subtypes of asthma by using targeted metabolomic analysis. Methods Demographic and clinical data were collected from 51 patients with asthma between January 2015 and December 2015. Routine blood and sputum induction tests were performed. Eosinophilic asthma was defined as induced sputum containing ≥ 3% eosinophils, and neutrophilic asthma, as induced sputum containing ≥ 71% neutrophils. Serum metabolic glycerophospholipid profile was determined by liquid chromatography-mass spectrometry. Differences in glycerophospholipid levels between eosinophilic and non-eosinophilic asthma and between neutrophilic and non-neutrophilic asthma were analyzed using partial least squares discriminant analysis. Results The serum lysophosphatidylglycerol level was significantly higher in the group with ≥ 3% eosinophils in sputum than in the group with < 3% eosinophils in sputum. The area under the receiver-operating characteristic curve was ≥ 70%. There was no significant difference in the serum metabolic glycerophospholipid profile between the group with sputum neutrophils ≥ 71% and the group with sputum neutrophils < 71%. Conclusion Serum lysophosphatidylglycerol is produced abundantly in eosinophilic asthma and may be a biomarker of eosinophilic asthma. This information is helpful for identifying and tailoring treatment for the common asthma subtypes.
基金Supported by Natural Science Foundation of Shaanxi Province, China (No. 2011JM4048)
文摘AIM: To investigate the levels of serum soluble intercellular adhesion molecules-1 (sICAM-1) and neutrophilic expression of CD18 in patients with various stages of diabetic retinopathy and to determine their different expression pattern in the development of diabetic retinopathy(DR). METHODS: Levels of serum sICAM-1 and CD18 on the surface of neutrophile were measured in 41 DR patients, they were classified in three subgroups according to the stage of retinopathy as determined by fund's ophthalmoscopy; 10 control subjects were also studied. sICAM-1 were measured by enzyme-linked immunosorbent assay and CD18 by flow cytometry. RESULTS: The neutrophilic CD18 expression and serum sICAM-1 level were all significantly elevated in all diabetic subgroups compared to control subjects (P <0.01). The differences of CD18 and sICAM-1 among the diabetic subgroups were significant in CD18 but not in sICAM-1. The progression of retinopathy was associated with an increase both in CD18 and in sICAM-1 levels by simple correlation analysis (beta =0.74, P<0.001; beta =0.38, P<0.01, respectively). But stepwise multiple regression analysis revealed that only CD18 Was independent determinant of retinopathy (beta =1.04, P<0.01). CONCLUSION: Our results confirm the contribution of endothelial and neutrophilic activation in the development of DR as indicated by increased levels of CD18 and sICAM-1. However, a direct implication of CD18 and ICAM-1 in the progression of DR can be supported only in the CD18 but not ICAM-1. CD18 and ICAM-1 may play different role in the development of diabetic retinopathy.
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
文摘BACKGROUNDChronic neutrophilic leukemia (CNL) is a rare bone marrow proliferative tumorand a heterogeneous disorder. In 2016, the World Health Organization includedactivating mutations in the CSF3R gene as one of the diagnostic criteria, withCSF3R T618I being the most common mutation. The disease is often accompaniedby splenomegaly, but no developmental abnormalities and significant reticularfibrosis, and no Ph chromosome and BCR-ABL fusion gene. So, it is difficult todiagnose at the first presentation in the absence of classical symptoms. Herein wedescribe a rare CNL patient without splenomegaly whose initial diagnostic cluewas neutrophilic hyperactivity.CASE SUMMARYThe patient is an 80-year-old Han Chinese man who presented with one month offatigue and fatigue aggravation in the last half of the month. He had nosplenomegaly, but had persistent hypofibrinogenemia, obvious skin bleeding, andhemoptysis, and required repeated infusion of fibrinogen therapy. After manyrelevant laboratory examinations, histopathological examination, and sequencinganalysis, the patient was finally diagnosed with CNL [CSF3R T618I positive:c.1853C>T (p.T618I) and c.2514T>A (p.C838)].CONCLUSIONThe physical examination and blood test for tumor-related genes are insufficientto establish a diagnosis of CNL. Splenomegaly is not that important, buthyperplasia of interstitial neutrophil system and activating mutations in CSF3Rare important clues to CNL diagnosis.
文摘Purpose of the study: Research of the clinical and diagnostic significance of determination of Lipocalin-2 associated with neutrophilic gelatinases (uNGAL) in the urine of children with urinary tract infection (UTI) and pyelonephritis. Materials and methods: We examined 30 children with acute pyelonephritis and UTI aged 1 to 16 years (average age 7.32 ± 4.52) including 26 girls and 4 boys. Verification of the diagnosis was conducted on the basis of clinical and laboratory data, medical history and instrumental examination of patients. All children were divided into 2 groups: 1st group—15 children with acute pyelonephritis, 2nd group—15 children with urinary tract infection. uNGAL was measured in the urine by enzyme-linked immunosorbent assay (EISA) (BioVendor Laboratoty Medicine). Results: It is found, that the urine level of NGAL depends on the damage degree of renal parenchyma. The correlation of medium strength was found between the excretion level of uNGAL during the acute period of pyelonephritis and the detection of renal scars according to the DMSA-nephroscintigraphy data. In the group of children with the acute pyelonephritis the direct correlation of medium strength was found between the excretion level of uNGAL/creatinine and leukocytosis value and also with the CRP blood level. Conclusion: The results allow us to recommend the determination of the excretion level of uNGAL/creatinine as an additional non-invasive marker for the early detection of renal parenchyma injury.
基金Beijing Xisco Clinical Oncology Research Foundation Project No.:Y-HR2018-271.
文摘Objective:By comparing the efficacy of different frequency application of polyethylene glycol recombinant human granulocyte stimulating factor in the prevention of neutropenia after chemotherapy with dose-intensive regimen in breast cancer, the more optimized administration scheme of polyethylene glycol recombinant human granulocyte stimulating factor in the prevention of neutropenia after chemotherapy in breast cancer was further explored.Methods:From June 2017 to May 2019, 64 patients with breast cancer who had received dose-intensive chemotherapy from June 2017 to May 2019 were randomly divided into two groups: control group (n=31) and observation group (n=33). Control group: after dose-intensive chemotherapy, PEG-rhG-CSF was injected subcutaneously with 100μg/kg, and given 24 hours after chemotherapy. Observation group: after dose-intensive chemotherapy, PEG-rhG-CSF: 50μg/kg, was injected subcutaneously and given 24 hours and 72 hours after chemotherapy. With PEG-rhG-CSF on the number of neutrophils in the two groups and the incidence, duration, fever incidence and duration of neutropenia in the two groups were observed. The curative effect was evaluated after 2 cycles of treatment.Results: There was no significant difference in the number of neutrophils between the two groups before chemotherapy in the first cycle and the second cycle (P>0.05), but the neutrophils in the observation group decreased slowly on the 3rd day, 5th day, 10th day and 5th day and 10th day after the first cycle of chemotherapy, and there was significant difference between the two groups (P<0.001). In the second cycle, there was no significant difference in neutrophils between the two groups on the third day after chemotherapy (P<0.05). In the control group, 7 patients were delayed by the second week because the neutrophil value was less than 2.0109/ L. The time of chemotherapy was delayed in 5 patients in the observation group. The incidence of neutropenia in the control group and the observation group was 41.9% VS 12.1%, and the duration of neutropenia in the observation group was significantly shorter than that in the control group (3.25 ±0.84d VS 5.12 ±1.24d), and the incidence of neutropenia in the observation group was 41.9% VS 12.1%, the duration of neutropenia in the observation group was significantly shorter than that in the control group (3.25 ±0.84d VS 5.12 ±1.24d). The number of patients with fever in the control group and the observation group were 10 cases of VS, the incidence rate was 32.2% VS 12.1%, compared with the control group and the observation group, the incidence of febrile fever was 32.2% and 12.1%, respectively. The duration of fever in the observation group was significantly shorter than that in the control group (2.46 ±1.24 d VS 4.05 ±1.01).Conclusions: Low dose of PEG-rhG-CSF can increase the absolute value of neutrophils after multiple administration, and its curative effect is better than that of single administration in dose-intensive chemotherapy, and the incidence of neutropenia and associated fever is lower, which is worthy of further clinical study and promotion.
文摘Aim. To elucidate whether an inhibited superoxide production(O 2 ) of neutrophils induced by commercial lactate based peritoneal dialysates(PDS) could be corrected after a transient intracellular acidosis. Methods. The intracellular pH([pHi]) of human neutrophils incubatd in PDS was monitored with a spectrofluorometer with a pH sensitive dye (BCECF AM). Neutrophilic O 2 stimulated by zymosan was determined in PDS with the superoxide dismutase inhibitable ferricytochrome c reduction, using a spectrophotometer. Results. The severe intracellular acidosis induced within 5 min by PDS at an extracellular pH of 5.2 could be promptly and completely recovered by a neutralization of the pH of media. However, O 2 by neutrophils exposed to the PDS for as little as 5 min was drastically and persistently inhibited, even the acidic [pHi] of cells had been fully returned for 1h. Conclusions. The intracellular acidification of cells in the initial phase could be transient and reversible, but impaired cell functions, at least in part including O 2 generating system, might be consistent and irreversible in the early stage of the cellular acidosis in the peritoneal cavity of CAPD patients. The findings above may be of particular importance in both clinic and cell biology.
基金financially supported by NSFC(82374171 and 81570701)the Natural Science Foundation of Guangdong Province(2024A1515012945)the Key Laboratory of Model Animal Phenotyping and Basic Research in Metabolic Diseases(2018KSYS003).
文摘Metabolic dysfunction-associated steatohepatitis(MASH)is the progressive form of metabolic dysfunction-associated steatotic liver disease(MASLD),and closely associated with a high risk of liver-related morbidity and mortality.Although enhanced neutrophil infiltration of the liver is a histological hallmark of MASH,the morphological pattern of hepatic neutrophils and their relevance to the definition of MASH remain unknown.This clinicopathological study aimed to determine the association of neutrophilic crown-like structures(CLSs)in liver biopsies and evaluate their relevance to the histological diagnosis of MASH.A total of 483 morbidly obese adults who underwent bariatric surgery were recruited.Neutrophilic CLSs in liver biopsies were detected by immunohistochemistry for neutrophil elastase and proteinase 3.All participants were classified into 4 histological subgroups:no MASLD(118,24.4%),MASLD(76,15.7%),borderline MASH(185,38.3%),and definite MASH(104,21.5%).In the discovery cohort(n=379),the frequency of neutrophilic CLSs increased in line with the severity of liver disease.The number of neutrophilic CLSs was positively correlated with established histological characteristics of MASH.At a cutoff value of<0.3 per 20×microscopic field,the number of neutrophilic CLSs yielded a robust diagnostic accuracy to discriminate no MASLD and MASLD from borderline MASH and definite MASH;a cutoff at>1.3 per 20×microscopic field exhibited a statistically significant accuracy to distinguish definite MASH from other groups(no MASLD,MASLD,and borderline MASH).The significance of neutrophilic CLSs in identifying borderline MASH and definite MASH was confirmed in an external validation cohort(n=104).The frequency of neutrophilic CLSs was significantly higher than that of macrophagic CLSs.In conclusion,neutrophilic CLSs in the liver represent a typical histological characteristic of MASH and may serve as a promising indicator to improve the diagnostic accuracy of MASH during histological assessment of liver biopsies.
文摘Psoriasis and other inflammatory skin diseases remain challenging to manage,in part owing to an incomplete understanding of how stromal cells,including fibroblasts and adipocytes,shape the inflammatory milieu.In their recent study,Xia et al.revealed an unexpected dual role for dermal adipocyte lineage cells,describing how these cells first promote and later restrain neutrophil-driven inflammation through a dynamic interplay of chemokine production and lipid-mediated resolution[1].
基金supported by the National Key R&D Program of China(2023YFC2508102)the National Natural Science Foundation of China(82373879)+3 种基金the Fujian Provincial Natural Science Foundation of China(2024J011009)the Xiamen University Double First Class Construction Project(Biology)(DFC2024004)supported by the Yunnan University Medical Research Foundation(YDYXJJ2024-0022)Yunnan Provincial Department of Education Scientific Research Fund Project(2025J0020).
文摘The immune response of the skin to danger signals involves rapid recruitment of neutrophils,but their excessive accumulation leads to inflammatory skin diseases,such as psoriasis;however,the mechanisms governing their initiation and resolution are poorly understood.Here,we revealed a dynamic immunoregulatory role of dermal white adipose tissue(dWAT)in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model.During inflammation onset,dWAT repopulates PDGFRA+preadipocytes(pAds),which secrete CXCL1 and SAA3,attracting and activating CXCR2+neutrophils.These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway,establishing a self-sustaining inflammatory loop.Paradoxically,prolonged IL-1βsignaling triggers PPARγ-dependent adipogenesis,transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators.Inhibition of adipogenesis,via pharmacological or genetic inhibition of PPARγ,disrupts the formation of early adipocytes,prevents neutrophil regression,and exacerbates inflammation.Analysis of human psoriatic cells revealed a C/EBPδ+dermal fibroblast(dFB)subpopulation enriched with preadipocytes,the IL-1 pathway,and inflammatory gene signatures.Furthermore,transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis.Together,our findings reveal the dual role of dWAT:PDGFRA+pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils,whereas PPARγ-driven adipogenesis resolves this process through lipid mediators.This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases,such as psoriasis and ulcers.
基金supported by a grant from the National Cancer Institute(R03CA252818 to NN).
文摘Introduction:Neutrophilic panniculitis(NP)is a rare subtype of neutrophilic dermatosis,a group of neutrophilrich inflammatory skin disorders that can present in association with myeloid neoplasms.NP is defined by the presence of a neutrophilic infiltrate in the fat lobules of the subcutis in the absence of either infection or vasculitis.We herein describe a 65-year-old woman with a recent diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome(MDS/MPN)who abruptly developed painful,pruritic nodules consistent with NP.Case presentation:A 65-year-old woman with MDS/MPN presented for evaluation of painful and pruritic nodules on her upper and lower extremities.A biopsy revealed a lobular neutrophilic infiltrate in the subcutis without evidence of microorganisms or vasculitis.The patient was diagnosed with NP and treated with oral prednisone.Within 1 month of treatment,she reported complete resolution of the nodules.Discussion:Similar to other neutrophilic dermatoses,NP may arise in association with hematologic malignancies of myeloid origin,such as MDS/MPN.A literature review revealed that most cases of NP associated with MDS occur after the onset of MDS and respond to systemic corticosteroids,not antibiotics.Infection should be ruled out before initiating treatment with systemic steroids.Conclusion:Although the mechanism is still unknown,it is important for clinicians to be aware that NP is associated with MDS;thus,hematological malignancies should be investigated on diagnosis of NP.Once diagnosed,NP is easily treated and has an excellent response to systemic corticosteroids.
基金Supported by the Key Scientific and Technological Project of Shandong Province(No.2014GSF119012)China
文摘Objective:To investigate the effects of ligustrazine(LTZ)on airway inflammation in a mouse model of neutrophilic asthma(NA).Methods:Forty healthy C57 BL/6 female mice were randomly divided into 4 groups using a random number table,including the normal control,NA,LTZ and dexamethasone(DXM)groups,with 10 rats in each group.The NA mice model was established by the method of ovalbumin combined with lipopolysaccharide sensitization.At 0.5 h before each challenge,LTZ and DXM groups were intraperitoneally injected with LTZ(80 mg/kg)or DXM(0.5 mg/kg)for 14 d,respectively,while the other two groups were given the equal volume of normal saline.After last challenge for 24 h,the aerosol inhalation of methacholine was performed and the airway reactivity was measured.The bronchoalveolar lavage fluid(BALF)was collected.The Wright-Giemsa staining was used for total white blood cells and differential counts.The levels of cytokines interleukin(IL)-17 and IL-10 were detected by enzyme-linked immunosorbent assay.The pathological change of lung tissue was observed by hematoxylin eosin staining.Results:The airway responsiveness of the NA group was significantly higher than the normal control group(P<0.05),while those in the LTZ and DXM groups were significantly lower than the NA group(P<0.05).The neutrophil and eosinophil counts in the LTZ and DXM groups were significantly lower than the NA group(P<0.05),and those in the LTZ group were significantly lower than the DXM group(P<0.05).There were a large number of peribronchiolar and perivascular inflammatory cells in filtration in the NA group.The airway inflammation in the LTZ and DXM groups were significantly alleviated than the NA group.The infiltration in the LTZ group was significantly reduced than the DXM group.Compared with the normal control group,the IL-17 level in BALF was significantly increased and the IL-10 level in BALF was significantly decreased in the NA group(P<0.05).LTZ and DXM treatment significantly decreased IL-17 levels and increased IL-10 levels compared with the NA group(P<0.05),and the changes in the above indices were more significant in the LTZ group(P<0.05).Conclusion:LTZ could alleviate the airway inflammation in the NA mice model through increasing the IL-10 level and decreasing the IL-17 level.
文摘Objective To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia （CNL）. Data sources Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms ＂chronic neutrophilic leukemia＂ and ＂diagnosis＂ were used for the literature search. Study selection We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL. Results The discovery of high-frequency granulocyte-colony stimulating factor receptor （CSF3R） mutations in CNL identifies a new major diagnostic criterion, and lends more specificity to the World Health Organization （WHO） diagnostic criteria for CNL, which are variably applied in routine clinical practice. Conclusions In patients for whom the cause of neutrophilia is not easily discerned, the incorporation of CSF3R mutation testing can be a useful point-of-care diagnostic to evaluate the presence of a clonal myeloid disorder, as well as providing the potential for genetically informed therapy. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of the SRC family-TNK2 and JAK kinases and may provide a new avenue for therapy.
文摘Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen species,degranulation,and NETosis(formation of neutrophil extracellular traps[NETs]).NETs,which contain antimicrobial compounds such as myeloperoxidase(MPO),represent a strategy to combat infection.However,excessive production of NETs promotes thrombosis,diabetes mellitus,and other diseases.Therefore,investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders.Here,we identified a novel NETosis inducer,human serum albumin(HSA)modified by the MPO product hypochlorous acid(HSAHOCl),whose accumulation in vivo was correlated with inflammatory processes.Using human blood neutrophils,we investigated HSAHOCl-induced NETosis and detected NET formation by flow cytometry.The results showed that the mechanism of HSAHOClinduced NETosis involved MPO,NADPH oxidase,and phosphatidylinositol 3-kinases(PI3Ks),and that HSAHOCl activated a reactive oxygen species-dependent suicidal type of NETosis.Moreover,HSAHOCl-induced NETosis was inhibited by an anti-HSAHOCl monoclonal antibody.Thus,our findings may facilitate the development of strategies to modulate NETosis in inflammation associated with elevated MPO activity.
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金supported by National High Level Hospital Clinical Research Funding,grant nos.BJ-2025-122,BJ2023-126CAMS Innovation Fund for Medical Sciences(CIFMS),grant no.2021-I2M-1050National Natural Science Foundation of China,grant no.82170956。
文摘Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microbial inflammatory disease,the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown.Here,we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology,cha racterized by poorer respiratory function,thicke ned bronchial walls,and increased neutrophils infiltration in lung tissue.Mechanistically,periodontitis pathogen Porphyromonas gingivalis(P.gingivalis)relocated in the lung through the respiratory tract and LPS from P.gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils.Furthermore,exposure to P.gingivalis of infiltrated neutrophils released matrix metallopeptidase-8(MMP-8)and neutrophil elastase(NE),which aggravated airway inflammation and tissue damage.These findings indicated that periodontitis could exacerbate COPD via its pathogen P.gingivalis,which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.
基金Natural Science Foundation of Beijing,No.7244428(to WZ)Peking University Medicine Sailing Program for Young Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+1 种基金the National Natural Science Foundation of China,Nos.81873784(to DF),82071426(to DF)Clinical Cohort Construction Program of Peking University Third Hospital,Nos.BYSYDL2019002(to DF)and BYSYZD2021004(to DF).
文摘Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.
基金supported by the Main Research Program(E0210202-05)of the Korea Food Research Institute(KFRI),funded by the Korean Ministry of Science and ICT.
文摘Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for pathogen clearance,aberrant NETosis has emerged as a critical modulator of acute and chronic respiratory pathologies,including acute respiratory distress syndrome,asthma,and chronic obstructive pulmonary disease.Dysregulated NET release exacerbates airway inflammation by inducing epithelial injury,mucus hypersecretion,and the recruitment of inflammatory leukocytes,thereby accelerating tissue remodeling and functional decline.Mechanistically,NETosis is governed by peptidyl arginine deiminase 4(PADI4)-mediated histone citrullination,NADPH oxidase-dependent reactive oxygen species production,mitochondrial metabolic reprogramming,and activation of toll-like receptors and inflammasomes.These molecular events perpetuate inflammation and prevent its resolution.Emerging evidence indicates that natural bioactive compounds,such as flavonoids,terpenoids,and polyphenols,attenuate NETosis by modulating oxidative stress,inhibiting PADI4 activation,or suppressing downstream pro-inflammatory cascades.Collectively,these findings highlight the therapeutic potential of targetingNETosis tomitigate neutrophil-driven airway pathology.This review aims to comprehensively synthesize recent mechanistic insights into NETosis and to delineate how modulation of NET formation contributes to the prevention and treatment of inflammatory respiratory diseases.
基金The National Natural Science Foundation of China(No.82130027,82301020,82100966)Young Elite Scientists Sponsorship Program by CAST(2024QNRC001)+5 种基金The China Postdoctoral Science Foundation(2023M732283)The National Key Research and Development Program of China(No.2023YFC2413600)The Shanghai Sailing Program(23YF1422000,21YF1424400)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212400)Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)Shanghai Pujiang Program(24PJD054).
文摘Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing.A unique Il4ra^(+)Ccl2^(high) neutrophil subset drove intense postinjury TRPV1^(+)nociceptive ingrowth,which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4(LXA4)in osteoblasts.Mechanistically,osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide(CGRP)suppressed the nuclear translocation of arachidonate 5-lipoxygenase(5-LOX)to favor the LXA4 biosynthesis.Moreover,in alveolar bone from patients with Type Ⅱ diabetes,we found diminished nociceptive innervation correlated with reduced autophagy,increased inflammation,and impaired bone formation.Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice.These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.
基金Guangdong Basic and Applied Basic Research Foundation,No.2023A1515110543(to XK)National Natural Science Foundation of China,Nos.82471335 and 82171307(to ZL)+3 种基金Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0504803(to ZL)Science and Technology Program of Guangzhou,No.202201020588(to ZL)China Postdoctoral Science Foundation,No.2023M744023(to MH)Guangzhou Municipal School(Hospital)Joint Funding(Dengfeng Hospital)Municipal Key Laboratory Construction Project,No.202102010009(to ZL).
文摘Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy,and there is a lack of targeted therapies.Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease,acute ischemic stroke,and Parkinson’s disease.In addition,mesenchymal stem cell therapy modulates the immune system,reduces neuroinflammation,and improves resolution of brain lesions by cells of the macrophage lineage.Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition,which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation.Therefore,we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response.In this study,we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy(Tg-SwDI/B).Bone marrow mesenchymal stem cell treatment improved cognitive function,reduced neuroinflammation,and maintained blood-brain barrier integrity in Tg-SwDI/B mice.Mechanistically,bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes,in a process known as mitocytosis,thereby preserving mitochondrial quality within the neutrophils.Mitochondrial damage in neutrophils leads to cellular injury,including the generation of reactive oxygen species and the formation of neutrophil extracellular traps.Neutrophils activate mitocytosis to promote mitochondrial renewal,which further enhances their own clearance by macrophage lineage cells.Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy,as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.
