In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing i...In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing is complex and involves a coordinated series of biological events,including inflammation,cell proliferation,and tissue remodeling.The innate immune system is important in the early stages of wound repair,with inflammation being a crucial initial phase in tissue rege-neration.However,the inflammatory response should be regulated,as excessive or dysregulated inflammation can impair healing.Platelet concentrates,specifi-cally PRF,have originated as promising tools to optimize the tissue repair process.PRF is a second-generation platelet concentrate,and the release of growth factors(GFs)plays a determining role in several aspects of wound healing,including promoting cell proliferation,stimulating angiogenesis,and modulating inflam-mation.PRF forms a fibrin matrix that entraps platelets and GFs.This structure allows for their sustained release over time,which is believed to provide a more favorable microenvironment for tissue repair.Recent research by Sá-Oliveira et al has provided valuable evidence supporting the efficacy of PRF in promoting wound healing.Their study,conducted on an animal model,demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process,enhancing tissue repair,and modulating the inflammatory response.We explore how PRF's unique properties contribute to a more controlled and effective healing process.By examining these findings,we aim to highlight PRF's potential as a promising therapeutic strategy for improved wound management.展开更多
Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive imm...Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.展开更多
Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polariz...Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polarization,to train the innate immune system by epigenic modification have been reported in laboratory animal research.Methods:In the current in vitro research,murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus,a coronavirus existed in mouse.At 3-,6-,12-,24-,and 48-h post infection(hpi.),the attached cells were washed with PBS and harvested in Trizol reagent.Then The harvest is subjected to transcriptome sequencing.Results:The transcriptome analysis showed the immediate(3 hpi.)up regulation of DEGs related to inflammation,like Il1b and Il6.DEGs related to M2 differential po-larization,like Irf4 showed up regulation at 24 hpi.,the late term after viral infection.In addition,DEGs related to metabolism and histone modification,like Ezh2 were de-tected,which might correlate with the trained immunity of macrophages.Conclusions:The current in vitro viral infection study showed the key innated im-munity character of macrophages,which suggested the replacement value of viral infection cells model,to reduce the animal usage in preclinical research.展开更多
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of prot...Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.展开更多
Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation.Mitochondria regulate macrophage activation and innate immun...Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation.Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases,including cochlear inflammation.The distribution,number,and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions,including noise exposure,ototoxicity,and age-related degeneration.However,the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear.Here,we summarize the major factors and mitochondrial signaling pathways(e.g.,metabolism,mitochondrial reactive oxygen species,mitochondrial DNA,and the inflammasome)that influence macrophage activation in the innate immune response.In particular,we focus on the properties of cochlear macrophages,activated signaling pathways,and the secretion of inflammatory cytokines after acoustic injury.We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.展开更多
Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multipl...Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multiple alleles of mpk4 and mekkl that exhibit cell death and constitutive defense responses. Bimolecular fluorescence complemen- tation （BiFC） analysis showed that both MPK4 and MEKK1 interact with MKK1 and MKK2, two closely related MAPK kinases, mkkl and mkk2 single mutant plants do not have obvious mutant phenotypes. To test whether MKK1 and MKK2 function redundantly, mkkl mkk2 double mutants were generated. The mkkl mkk2 double mutant plants die at seedling stage and the seedling-lethality phenotype is temperature-dependent. Similar to the mpk4 and mekkl mutants, the mkkl mkk2 double mutant seedlings accumulate high levels of H202, display spontaneous cell death, constitutively express Pathogenesis Related （PR） genes and exhibit pathogen resistance. In addition, activation of MPK4 by fig22 is impaired in the mkkl mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants.展开更多
AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate imm...AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.展开更多
Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex inter...Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.展开更多
BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori(H.pylori)infection and increased risk of gastric cancer.AIM To identify the risk factors associated with H.pylori infe...BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori(H.pylori)infection and increased risk of gastric cancer.AIM To identify the risk factors associated with H.pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children.METHODS We performed a study of 155 children with digestive symptoms,who were divided into two groups according to the histopathological exam:Group 1–48 children with H.pylori-induced chronic gastritis,and Group 2–control group.RESULTS Rural area and poor living conditions were significantly associated with H.pylori chronic gastritis(P=0.0042/P<0.0001).Both positive immunoglobulin A anti H.pylori and the rapid urease test were significantly associated with H.pylori infection(P<0.0001).Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H.pylori chronic gastritis(P=0.111/P=0.284).We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils(P=0.0225/P=0.0292).CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.展开更多
Here, we investigated the effect of dietary arginine（Arg） supplementation on innate immunity and the antioxidant ability of broiler chickens. The experiment was designed as a single-factorial arrangement（n=8 cages/...Here, we investigated the effect of dietary arginine（Arg） supplementation on innate immunity and the antioxidant ability of broiler chickens. The experiment was designed as a single-factorial arrangement（n=8 cages/treatment, six birds/cage）, and we used four dietary Arg concentrations（10.0, 15.0, 20.0 or 25.0 g kg–1）. On day 21, the birds were killed to obtain spleen, cecal tonsil and liver samples to determine the gene expression and antioxidant characteristics. Increasing the Arg concentration linearly decreased（P0.05） the m RNA expression of splenic interleukin-18（IL-18） and tumor necrosis factor-α（TNF-α）. Dietary Arg supplementation quadratically decreased（P0.05） the expression of interleukin-1b（IL-1b） and interferon-γ（IFN-γ） m RNA in the spleen. Increasing Arg concentrations linearly and quadratically reduced the expression of IL-18 m RNA in the spleen. Meanwhile, increasing dietary Arg supplementation linearly and quadratically increased the lymphotactin m RNA（P0.05） expression, and linearly increased the macrophage inflammatory protein-1β（MIP-1β） and toll-like receptor 15（TLR15） m RNA expression in the cecal tonsils. Dietary Arg supplementation linearly（P0.05） increased the glutathione peroxidase（GSH-Px）, catalase（CAT）, and lysozyme（LZM） activities in the liver. However, the malondialdehyde（MDA） activity in the liver was not influenced by the dietary Arg concentration（P0.05）. No significant（P0.05） effect was found on the activity of superoxide dismutase（SOD） in the liver. Thus high levels of Arg supplementation（20.0 g kg^（–1）） may potentially suppress the innate immunity of broiler chickens, and dietary Arg supplementation enhances the antioxidant activity in broiler chickens.展开更多
· AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus(A. fumigatus) in cultured human corneal epithelial cells(HCECs), and whether C-type lectin recept...· AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus(A. fumigatus) in cultured human corneal epithelial cells(HCECs), and whether C-type lectin receptor Dectin-1 mediates the immunomodulatory effects of curdlan.·METHODS: The HCECs were stimulated by curdlan in different concentrations(50, 100, 200, 400 μg/m L) for various time. Then HCECs pretreated with or without laminarin(Dectin-1 blocker, 0.3 mg/m L) and curdlan were stimulated by A. fumigatus hyphae. The m RNA and protein production of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6) were determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The protein level of Dectin-1 was measured by Western blot.· RESULTS: Curdlan stimulated m RNA expression of TNF-α and IL-6 in a dose and time dependent manner in HCECs. Curdlan pretreatment before A. fumigatus hyphae stimulation significantly enhanced the expression of TNF-α and IL-6 at m RNA and protein levels compared with A. fumigatus hyphae stimulation group(P 【0.05).Both curdlan and A. fumigatus hyphae up-regulated Dectin-1 protein expression in HCECs, and Dectin-1expression was elevated to 1.5- to 2-fold by curdlan pretreatment followed hyphae stimulation. The Dectin-1blocker laminarin suppressed the m RNA expression and protein production of TNF-α and IL-6 induced by curdlan and hyphae(P 【0.05).· CONCLUSION: These findings demonstrated that curdlan pretreatment enhanced the inflammatory response induced by A. fumigatus hyphae in HCECs.Dectin-1 is essential for the immunomodulatory effectsof curdlan. Curdlan may have high clinical application values in fungal keratitis treatment.展开更多
Background： The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growt...Background： The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid（FA） metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as wel as genes involved with FA metabolism, immunity and cel ular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil：lymphocyte ratios, relative organ weights and bodyweight data were also compared.Results： Broiler bodyweight（n = 12） was four times that of layers（n = 12） by d 14 and had significantly higher carcass fat percentage compared to the cross（n = 6; P = 0.002） and layers（P = 0.017） which were not significantly different from each other（P = 0.523）. The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite al being raised on the same diet. Genes associated with FA synthesis andβ-oxidation were upregulated in the broilers compared to the layers indicating a net overal increase in FA metabolism,which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as wel as organel e stress indicators ERN1 and XBP1 were found to be nonsignificant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additional y there was no difference in heterophil： lymphocytes between any of the birds.Conclusions： The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cel ular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.展开更多
AIM： To explore the effects of retinoic acid receptor-γ （RARγ） on innate immune responses against Aspergillus fumigatus （A. fumigatus） in cultured human corneal epithelial cells （HCECs）. METHODS： The HCECs ...AIM： To explore the effects of retinoic acid receptor-γ （RARγ） on innate immune responses against Aspergillus fumigatus （A. fumigatus） in cultured human corneal epithelial cells （HCECs）. METHODS： The HCECs were stimulated with A. fumigatus hyphae for 0, 2, 4, 8, 12 and 16h. RARγ mRNA and protein levels were tested by quantitative real-time polymerase chain reaction （qRT-PCR） and Western blot. Then HCECs were pretreated with or without BMS961 （RARγ agonist, 1 μg/mL）. The mRNA and protein expression of Dectin-1 and the downstream cytokines （TNF-α and IL-6） were determined by qRT-PCR, Western blot and enzyme-linked immunosorbent assay （ELISA）. RESULTS： The expression of RARγ was upregulated after stimulation with A. fumigatus. RARγ mRNA began to rise at 4h and peaked at 8h （P〈0.001）. The protein of RARγ reached to the peak at 16h （P〈0.001）. Pretreated with BMS961 before A. fumigatus hyphae stimulation, expression of Dectin-1, TNF-α and IL-6 decreased dramatically at mRNA and protein levels. CONCLUSION： HCECs can express RARγ and A. fumigatus hyphae infection can increase RARγ expression. BMS961 can inhibit the expression of Dectin-1 and pro-inflammatory cytokines, and play an anti-inflammatory role in innate immune responses against A. fumigatus.展开更多
Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for h...Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.展开更多
The Really Interesting New Gene (RING) ubiquitin E3 ligase family comprises a large number of members and plays a crucial role in the antiviral process. RING finger protein 115 (RNF115), also known as BCA2, Rabring7, ...The Really Interesting New Gene (RING) ubiquitin E3 ligase family comprises a large number of members and plays a crucial role in the antiviral process. RING finger protein 115 (RNF115), also known as BCA2, Rabring7, or ZNF364, is a novel RING domain protein. In this paper, we cloned the RNF115 homologue from black carp (Mylopharyngodon piceus) and characterized it. The open reading frame of black carp RNF115 contains 933 nucleotides and encodes 310 amino acids. The C-terminal RING domain of RNF115 is highly conserved among various homologous species. Immunofluorescence assays revealed the cytoplasmic and nuclear distribution of RNF115 in the presence or absence of spring viremia of carp virus (SVCV) infection. Overexpression of RNF115 impaired interferon (IFN) and the related interferon-stimulated gene (ISG) mRNA expression, while upregulating SVCV replication. Ex vivo knockdown of RNF115 offered the host cells enhanced antiviral signaling. In vivo knockdown of RNF115 also strengthened black carp's antiviral capacity. Additionally, the results of a dual-luciferase reporter assay, plaque assay, and qRT-PCR assay demonstrated that co-transfection of RNF115 with IRF3/7 reduced IRF3/7-induced IFN transcription and antiviral ability. The association between RNF115 and IRF3/7 was detected by co-immunoprecipitation and immunofluorescence assays. Co-transfection of RNF115 with IRF3/7 also reduced the protein levels of IRF3/7, which were rescued by MG132. The enhanced K48-linked ubiquitination of IRF3/7 under the condition of RNF115 co-transfection implied the ubiquitin/proteasome degradation pathway catalyzed by RNF115. Cysteine 238 and 241 in the RING domain are the main enzyme active sites for RNF115, and the mutant C238/241A lost most of its ability to restrict IRF3/7. In conclusion, black carp RNF115 dampens IRF3/7-mediated IFN signaling through facilitating the ubiquitination and degradation of IRF3/7, which sheds light on the regulation of IFN signaling.展开更多
Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a ...Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.展开更多
Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanost...Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.展开更多
Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory ha...Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.展开更多
Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary d...Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.展开更多
Trained immunity is a phenomenon in which brief exposure to an infectious agent or a vaccine can induce long-lasting changes in the host’s immune system,enhancing protection against subsequent infections.The concept ...Trained immunity is a phenomenon in which brief exposure to an infectious agent or a vaccine can induce long-lasting changes in the host’s immune system,enhancing protection against subsequent infections.The concept of trained immunity has a significant impact on the field of immunology and has the potential to revolutionize how we approach vaccination and infectious disease control.Investigations into trained immunity are rapidly advanc-ing and have led to the development of new vaccines and immunotherapeutic strategies that harness the power of this phenomenon.While more investigations are needed to fully understand the mechanisms of trained immunity and its potential limitations,the prospects for its future application in clinical practice are promising.Here,we describe trained immunity as a biological process and explore the innate cues,epigenetic changes,and metabolic reprogram-ming activities that affect how trained immunity is induced.展开更多
基金Supported by The Oman Ministry of Higher Education,Research,and Innovation,No.BFP/RGP/HSS/24/015.
文摘In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing is complex and involves a coordinated series of biological events,including inflammation,cell proliferation,and tissue remodeling.The innate immune system is important in the early stages of wound repair,with inflammation being a crucial initial phase in tissue rege-neration.However,the inflammatory response should be regulated,as excessive or dysregulated inflammation can impair healing.Platelet concentrates,specifi-cally PRF,have originated as promising tools to optimize the tissue repair process.PRF is a second-generation platelet concentrate,and the release of growth factors(GFs)plays a determining role in several aspects of wound healing,including promoting cell proliferation,stimulating angiogenesis,and modulating inflam-mation.PRF forms a fibrin matrix that entraps platelets and GFs.This structure allows for their sustained release over time,which is believed to provide a more favorable microenvironment for tissue repair.Recent research by Sá-Oliveira et al has provided valuable evidence supporting the efficacy of PRF in promoting wound healing.Their study,conducted on an animal model,demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process,enhancing tissue repair,and modulating the inflammatory response.We explore how PRF's unique properties contribute to a more controlled and effective healing process.By examining these findings,we aim to highlight PRF's potential as a promising therapeutic strategy for improved wound management.
基金Supported by Shenzhen Medical Research Fund,No.D2301010Shenzhen Science and Technology Program,No.RCYX20231211090346060。
文摘Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.
基金CAMs innovation Fund for Medical Sciences,Grant/Award Number:2022-12M-CoV19-005National Key Projects,Grant/Award Number:2023YFF0724900 and 2021YFF0702802。
文摘Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polarization,to train the innate immune system by epigenic modification have been reported in laboratory animal research.Methods:In the current in vitro research,murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus,a coronavirus existed in mouse.At 3-,6-,12-,24-,and 48-h post infection(hpi.),the attached cells were washed with PBS and harvested in Trizol reagent.Then The harvest is subjected to transcriptome sequencing.Results:The transcriptome analysis showed the immediate(3 hpi.)up regulation of DEGs related to inflammation,like Il1b and Il6.DEGs related to M2 differential po-larization,like Irf4 showed up regulation at 24 hpi.,the late term after viral infection.In addition,DEGs related to metabolism and histone modification,like Ezh2 were de-tected,which might correlate with the trained immunity of macrophages.Conclusions:The current in vitro viral infection study showed the key innated im-munity character of macrophages,which suggested the replacement value of viral infection cells model,to reduce the animal usage in preclinical research.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.:82100801,81974096,81770711,81974097,and 81961138007).
文摘Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
基金supported by the China Postdoctoral Science Foundation(2022M712892)the Joint project Henan Province Medical Science and Technology Project(LHGJ20210297).
文摘Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation.Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases,including cochlear inflammation.The distribution,number,and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions,including noise exposure,ototoxicity,and age-related degeneration.However,the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear.Here,we summarize the major factors and mitochondrial signaling pathways(e.g.,metabolism,mitochondrial reactive oxygen species,mitochondrial DNA,and the inflammasome)that influence macrophage activation in the innate immune response.In particular,we focus on the properties of cochlear macrophages,activated signaling pathways,and the secretion of inflammatory cytokines after acoustic injury.We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.
文摘Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multiple alleles of mpk4 and mekkl that exhibit cell death and constitutive defense responses. Bimolecular fluorescence complemen- tation （BiFC） analysis showed that both MPK4 and MEKK1 interact with MKK1 and MKK2, two closely related MAPK kinases, mkkl and mkk2 single mutant plants do not have obvious mutant phenotypes. To test whether MKK1 and MKK2 function redundantly, mkkl mkk2 double mutants were generated. The mkkl mkk2 double mutant plants die at seedling stage and the seedling-lethality phenotype is temperature-dependent. Similar to the mpk4 and mekkl mutants, the mkkl mkk2 double mutant seedlings accumulate high levels of H202, display spontaneous cell death, constitutively express Pathogenesis Related （PR） genes and exhibit pathogen resistance. In addition, activation of MPK4 by fig22 is impaired in the mkkl mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants.
文摘AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.
基金Supported by Grants for"Asia-Oceania Collaborative Research Grants"from Kanae Foundation for the Promotion of Medical Science(to Kanda T)Grants for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology,Japan(to Kanda T)
文摘Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.
基金Supported by University of Medicine,Pharmacy,Sciences and Technology“George Emil Palade”of Târgu Mureş,Romania,No.293/6/14.01.2020.
文摘BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori(H.pylori)infection and increased risk of gastric cancer.AIM To identify the risk factors associated with H.pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children.METHODS We performed a study of 155 children with digestive symptoms,who were divided into two groups according to the histopathological exam:Group 1–48 children with H.pylori-induced chronic gastritis,and Group 2–control group.RESULTS Rural area and poor living conditions were significantly associated with H.pylori chronic gastritis(P=0.0042/P<0.0001).Both positive immunoglobulin A anti H.pylori and the rapid urease test were significantly associated with H.pylori infection(P<0.0001).Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H.pylori chronic gastritis(P=0.111/P=0.284).We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils(P=0.0225/P=0.0292).CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.
基金supported by the Laboratory of Animal Nutrition,Institute of Animal Sciences,Chinese Academy of Agricultural Sciences(CAAS)supported by the National Key Technology R&D Program of China(2012BAD39B01)the Agricultural Science and Technology Innovation Program of CAAS(ASTIP-IAS07)in China
文摘Here, we investigated the effect of dietary arginine（Arg） supplementation on innate immunity and the antioxidant ability of broiler chickens. The experiment was designed as a single-factorial arrangement（n=8 cages/treatment, six birds/cage）, and we used four dietary Arg concentrations（10.0, 15.0, 20.0 or 25.0 g kg–1）. On day 21, the birds were killed to obtain spleen, cecal tonsil and liver samples to determine the gene expression and antioxidant characteristics. Increasing the Arg concentration linearly decreased（P0.05） the m RNA expression of splenic interleukin-18（IL-18） and tumor necrosis factor-α（TNF-α）. Dietary Arg supplementation quadratically decreased（P0.05） the expression of interleukin-1b（IL-1b） and interferon-γ（IFN-γ） m RNA in the spleen. Increasing Arg concentrations linearly and quadratically reduced the expression of IL-18 m RNA in the spleen. Meanwhile, increasing dietary Arg supplementation linearly and quadratically increased the lymphotactin m RNA（P0.05） expression, and linearly increased the macrophage inflammatory protein-1β（MIP-1β） and toll-like receptor 15（TLR15） m RNA expression in the cecal tonsils. Dietary Arg supplementation linearly（P0.05） increased the glutathione peroxidase（GSH-Px）, catalase（CAT）, and lysozyme（LZM） activities in the liver. However, the malondialdehyde（MDA） activity in the liver was not influenced by the dietary Arg concentration（P0.05）. No significant（P0.05） effect was found on the activity of superoxide dismutase（SOD） in the liver. Thus high levels of Arg supplementation（20.0 g kg^（–1）） may potentially suppress the innate immunity of broiler chickens, and dietary Arg supplementation enhances the antioxidant activity in broiler chickens.
基金Supported by National Natural Science Foundation of China(No.81170825No.81470609)+2 种基金Natural Science Foundation of Shandong Province(No.ZR2013HQ007No.ZR2012HZ001)the Specialized Research Fund for the Doctoral Program of Higher Education,2012(No.20123706110003)
文摘· AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus(A. fumigatus) in cultured human corneal epithelial cells(HCECs), and whether C-type lectin receptor Dectin-1 mediates the immunomodulatory effects of curdlan.·METHODS: The HCECs were stimulated by curdlan in different concentrations(50, 100, 200, 400 μg/m L) for various time. Then HCECs pretreated with or without laminarin(Dectin-1 blocker, 0.3 mg/m L) and curdlan were stimulated by A. fumigatus hyphae. The m RNA and protein production of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6) were determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The protein level of Dectin-1 was measured by Western blot.· RESULTS: Curdlan stimulated m RNA expression of TNF-α and IL-6 in a dose and time dependent manner in HCECs. Curdlan pretreatment before A. fumigatus hyphae stimulation significantly enhanced the expression of TNF-α and IL-6 at m RNA and protein levels compared with A. fumigatus hyphae stimulation group(P 【0.05).Both curdlan and A. fumigatus hyphae up-regulated Dectin-1 protein expression in HCECs, and Dectin-1expression was elevated to 1.5- to 2-fold by curdlan pretreatment followed hyphae stimulation. The Dectin-1blocker laminarin suppressed the m RNA expression and protein production of TNF-α and IL-6 induced by curdlan and hyphae(P 【0.05).· CONCLUSION: These findings demonstrated that curdlan pretreatment enhanced the inflammatory response induced by A. fumigatus hyphae in HCECs.Dectin-1 is essential for the immunomodulatory effectsof curdlan. Curdlan may have high clinical application values in fungal keratitis treatment.
基金financially supported by the Australian Poultry Cooperative Research Centre
文摘Background： The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid（FA） metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as wel as genes involved with FA metabolism, immunity and cel ular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil：lymphocyte ratios, relative organ weights and bodyweight data were also compared.Results： Broiler bodyweight（n = 12） was four times that of layers（n = 12） by d 14 and had significantly higher carcass fat percentage compared to the cross（n = 6; P = 0.002） and layers（P = 0.017） which were not significantly different from each other（P = 0.523）. The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite al being raised on the same diet. Genes associated with FA synthesis andβ-oxidation were upregulated in the broilers compared to the layers indicating a net overal increase in FA metabolism,which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as wel as organel e stress indicators ERN1 and XBP1 were found to be nonsignificant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additional y there was no difference in heterophil： lymphocytes between any of the birds.Conclusions： The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cel ular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.
基金Supported by National Natural Science Foundation of China(No.81470609No.81500695+2 种基金No.81300730)Key Project of Natural Science Foundation of Shandong Province(No.ZR2012HZ001)Youth Natural Science Foundation of Shandong Province(No.ZR2013HQ007)
文摘AIM： To explore the effects of retinoic acid receptor-γ （RARγ） on innate immune responses against Aspergillus fumigatus （A. fumigatus） in cultured human corneal epithelial cells （HCECs）. METHODS： The HCECs were stimulated with A. fumigatus hyphae for 0, 2, 4, 8, 12 and 16h. RARγ mRNA and protein levels were tested by quantitative real-time polymerase chain reaction （qRT-PCR） and Western blot. Then HCECs were pretreated with or without BMS961 （RARγ agonist, 1 μg/mL）. The mRNA and protein expression of Dectin-1 and the downstream cytokines （TNF-α and IL-6） were determined by qRT-PCR, Western blot and enzyme-linked immunosorbent assay （ELISA）. RESULTS： The expression of RARγ was upregulated after stimulation with A. fumigatus. RARγ mRNA began to rise at 4h and peaked at 8h （P〈0.001）. The protein of RARγ reached to the peak at 16h （P〈0.001）. Pretreated with BMS961 before A. fumigatus hyphae stimulation, expression of Dectin-1, TNF-α and IL-6 decreased dramatically at mRNA and protein levels. CONCLUSION： HCECs can express RARγ and A. fumigatus hyphae infection can increase RARγ expression. BMS961 can inhibit the expression of Dectin-1 and pro-inflammatory cytokines, and play an anti-inflammatory role in innate immune responses against A. fumigatus.
文摘Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.
基金the institutional review board or ethics committee of Hunan Normal University (2024195)。
文摘The Really Interesting New Gene (RING) ubiquitin E3 ligase family comprises a large number of members and plays a crucial role in the antiviral process. RING finger protein 115 (RNF115), also known as BCA2, Rabring7, or ZNF364, is a novel RING domain protein. In this paper, we cloned the RNF115 homologue from black carp (Mylopharyngodon piceus) and characterized it. The open reading frame of black carp RNF115 contains 933 nucleotides and encodes 310 amino acids. The C-terminal RING domain of RNF115 is highly conserved among various homologous species. Immunofluorescence assays revealed the cytoplasmic and nuclear distribution of RNF115 in the presence or absence of spring viremia of carp virus (SVCV) infection. Overexpression of RNF115 impaired interferon (IFN) and the related interferon-stimulated gene (ISG) mRNA expression, while upregulating SVCV replication. Ex vivo knockdown of RNF115 offered the host cells enhanced antiviral signaling. In vivo knockdown of RNF115 also strengthened black carp's antiviral capacity. Additionally, the results of a dual-luciferase reporter assay, plaque assay, and qRT-PCR assay demonstrated that co-transfection of RNF115 with IRF3/7 reduced IRF3/7-induced IFN transcription and antiviral ability. The association between RNF115 and IRF3/7 was detected by co-immunoprecipitation and immunofluorescence assays. Co-transfection of RNF115 with IRF3/7 also reduced the protein levels of IRF3/7, which were rescued by MG132. The enhanced K48-linked ubiquitination of IRF3/7 under the condition of RNF115 co-transfection implied the ubiquitin/proteasome degradation pathway catalyzed by RNF115. Cysteine 238 and 241 in the RING domain are the main enzyme active sites for RNF115, and the mutant C238/241A lost most of its ability to restrict IRF3/7. In conclusion, black carp RNF115 dampens IRF3/7-mediated IFN signaling through facilitating the ubiquitination and degradation of IRF3/7, which sheds light on the regulation of IFN signaling.
基金supported by the Henan Provincial Science and Technology Research Project(grant number 221100310100 to Z.L.and X.H.).
文摘Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.
基金supported by the National Key Research and Development Program of China(Grant No.2021YFB3801000)the National Natural Science Foundation of China(Grant No.32030061)+3 种基金the Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406000)the Shanghai Sailing Program(Grant No.21YF1454200)Shanghai International Cooperation Project(Grant No.23490712900)All the animal experiments were performed with the approval of the Tongji University Experimental Animal Center,and the animal biomedical research authorization number is TJLAC-020-228.
文摘Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.
文摘Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.
文摘Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.
文摘Trained immunity is a phenomenon in which brief exposure to an infectious agent or a vaccine can induce long-lasting changes in the host’s immune system,enhancing protection against subsequent infections.The concept of trained immunity has a significant impact on the field of immunology and has the potential to revolutionize how we approach vaccination and infectious disease control.Investigations into trained immunity are rapidly advanc-ing and have led to the development of new vaccines and immunotherapeutic strategies that harness the power of this phenomenon.While more investigations are needed to fully understand the mechanisms of trained immunity and its potential limitations,the prospects for its future application in clinical practice are promising.Here,we describe trained immunity as a biological process and explore the innate cues,epigenetic changes,and metabolic reprogram-ming activities that affect how trained immunity is induced.
