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
In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express C...In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.展开更多
Acute lung injury （ALI） and its more severe form acute respiratory distress syndrome （ARDS） are acute clinical complications,which cause significant morbidity and mortality.1 Despite recent advances in our underst...Acute lung injury （ALI） and its more severe form acute respiratory distress syndrome （ARDS） are acute clinical complications,which cause significant morbidity and mortality.1 Despite recent advances in our understanding of the pathophysiology and diagnosis of ALI and ARDS,the clinical strategies are restricted to mechanical ventilation and supportive treatments,such as fluid conservative management and glucocorticoids （GCs）.Mechanical ventilation is a common and life-saving strategy for the patients with ARDS.Lung protective ventilation strategy with lower tidal volumes can improve hypoxia and reduce the mortality in patients with ARDS.展开更多
Scleritis and other autoimmune diseases are characterized by an imbalance in the levels of pro-inflammatory and anti-inflammatory molecules with the balance tilted more towards the former due to the failure of recogni...Scleritis and other autoimmune diseases are characterized by an imbalance in the levels of pro-inflammatory and anti-inflammatory molecules with the balance tilted more towards the former due to the failure of recognition of self. The triggering of inflammatory process could be ascribed to the presence of cytoplasmic DNA/chromatin that leads to activation of cytosolic DNA-sensing c GAS-STING(cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway and enhanced expression of NF-κB that results in an increase in the production of pro-inflammatory bioactive lipids. Bioactive lipids gamma-linolenic acid(GLA), dihomoGLA(DGLA), prostaglandin E1(PGE1), prostacyclin(PGI2) and lipoxin A4, resolvins, protectins and maresins have antiinflammatory actions, bind to DNA to render it non-antigenic and are decreased in autoimmune diseases. These results suggest that efforts designed to enhance the production of anti-inflammatory bioactive lipids may form a new approach to autoimmune diseases. Local injection or infusion of lipoxins, resolvins, protectins and maresins or their precursors such as arachidonic acid may be exploited in the prevention and management of autoimmune diseases including scleritis, uveitis and lupus/rheumatoid arthritis.展开更多
Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a pr...Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a proportion of patients,the systemic toxicity accompanied by longterm administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability,are still unsettled problems lying across the full remission of RA.So far,these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment.A variety of versatile nanocarriers with controllable physicochemical properties,tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment.This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance,pro-resolving therapy or regulating the immunometabolism for RA treatments.展开更多
Efferocytosis refers to the process that phagocytes recognize and remove the apoptotic cells,which is essential for maintaining tissue homeostasis both in physiological and pathological conditions.Numerous studies hav...Efferocytosis refers to the process that phagocytes recognize and remove the apoptotic cells,which is essential for maintaining tissue homeostasis both in physiological and pathological conditions.Numerous studies have demonstrated that efferocytosis can prevent secondary necrosis and proinflammatory factor release,leading to the resolution of inflammation and tissue immunological tolerance in numerous diseases such as stroke.Stroke is a leading cause of death and morbidity for adults worldwide.Persistent inflammation triggered by the dead cells or cell debris is a major contributor to post-stroke brain damage.Effective efferocytosis might be an efficient strategy to minimize inflammation and restore brain homeostasis for neuronal regeneration and function recovery.In this review,we will discuss the phagocytes in the brain,the molecular mechanisms underlying efferocytosis,the role of efferocytosis in inflammation resolution,and the potential therapeutic applications targeting efferocytosis in stroke.展开更多
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funded by institutional funds from the Georg-Speyer-Haus,the LOEWE Center Frankfurt Cancer Institute(FCl)funded by the Hessen State Ministry for Higher Education,Research and the Arts,as well as grants from the Deutsche Forschungsgemeinschaft(FOR2438:Gr1916/11-1,SFB1292-Project ID:318346496-TP16,SFB1479-Project ID:441891347-P02,GRK2336)the German Federal Ministry of Education and Research(BMBF+1 种基金01KD2206Q/SATURN3)the European Research Council(Advanced Grant PLASTICAN-101021078).
文摘In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.
文摘Acute lung injury （ALI） and its more severe form acute respiratory distress syndrome （ARDS） are acute clinical complications,which cause significant morbidity and mortality.1 Despite recent advances in our understanding of the pathophysiology and diagnosis of ALI and ARDS,the clinical strategies are restricted to mechanical ventilation and supportive treatments,such as fluid conservative management and glucocorticoids （GCs）.Mechanical ventilation is a common and life-saving strategy for the patients with ARDS.Lung protective ventilation strategy with lower tidal volumes can improve hypoxia and reduce the mortality in patients with ARDS.
文摘Scleritis and other autoimmune diseases are characterized by an imbalance in the levels of pro-inflammatory and anti-inflammatory molecules with the balance tilted more towards the former due to the failure of recognition of self. The triggering of inflammatory process could be ascribed to the presence of cytoplasmic DNA/chromatin that leads to activation of cytosolic DNA-sensing c GAS-STING(cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway and enhanced expression of NF-κB that results in an increase in the production of pro-inflammatory bioactive lipids. Bioactive lipids gamma-linolenic acid(GLA), dihomoGLA(DGLA), prostaglandin E1(PGE1), prostacyclin(PGI2) and lipoxin A4, resolvins, protectins and maresins have antiinflammatory actions, bind to DNA to render it non-antigenic and are decreased in autoimmune diseases. These results suggest that efforts designed to enhance the production of anti-inflammatory bioactive lipids may form a new approach to autoimmune diseases. Local injection or infusion of lipoxins, resolvins, protectins and maresins or their precursors such as arachidonic acid may be exploited in the prevention and management of autoimmune diseases including scleritis, uveitis and lupus/rheumatoid arthritis.
基金supported by the National Natural Science Foundation of China(No.82003661)。
文摘Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of RA.Nevertheless,the inadequate response to current therapies in a proportion of patients,the systemic toxicity accompanied by longterm administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability,are still unsettled problems lying across the full remission of RA.So far,these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment.A variety of versatile nanocarriers with controllable physicochemical properties,tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment.This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance,pro-resolving therapy or regulating the immunometabolism for RA treatments.
基金supported by grants from the National Natural Science Foundation of China(Nos.82071283,82371332,and 81801298)the Natural Science Foundation of Shanghai(No.22ZR1437700)+1 种基金the Research Program of Science and Technology Commission of Shanghai Municipality(No.201409005300)Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation(No.20DZ2254200).
文摘Efferocytosis refers to the process that phagocytes recognize and remove the apoptotic cells,which is essential for maintaining tissue homeostasis both in physiological and pathological conditions.Numerous studies have demonstrated that efferocytosis can prevent secondary necrosis and proinflammatory factor release,leading to the resolution of inflammation and tissue immunological tolerance in numerous diseases such as stroke.Stroke is a leading cause of death and morbidity for adults worldwide.Persistent inflammation triggered by the dead cells or cell debris is a major contributor to post-stroke brain damage.Effective efferocytosis might be an efficient strategy to minimize inflammation and restore brain homeostasis for neuronal regeneration and function recovery.In this review,we will discuss the phagocytes in the brain,the molecular mechanisms underlying efferocytosis,the role of efferocytosis in inflammation resolution,and the potential therapeutic applications targeting efferocytosis in stroke.
