Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates tha...Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.展开更多
Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage,but the role of interleukin-18(IL-18),a cytokine associated with inflammasome activation,in modulating the T-cell r...Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage,but the role of interleukin-18(IL-18),a cytokine associated with inflammasome activation,in modulating the T-cell response and autoimmune pathogenesis remains largely unclear.In this study,we detected high expression levels of the IL-18 receptorαchain(IL-18Rα)in murine and human Th17 cells.In culture,IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production,a phenotype of pathogenic Th17(pTh17)cells.Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures.Mechanistically,IL-18 promoted Stat3 phosphorylation,which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production.In patients with primary Sjögren’s syndrome(pSS)and systemic lupus erythematosus(SLE),IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity.Moreover,the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren’s syndrome(ESS)model mice and the renal tissues of lupus model mice.Furthermore,adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice,whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice.Together,our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development,indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.展开更多
基金the National Natural Science Foundation of China(Grant No.82071827)the Jiangsu Province Natural Science Foundation(Grant No.BK20210963).
文摘Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.
基金supported by the Hong Kong Research Grants Council(17116424,17111222,17103821)the National Natural Science Foundation of China(82471821,82171771,82572073 and 82572074)the Sanming Project of Medicine in Shenzhen(No.SZSM202111006)。
文摘Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage,but the role of interleukin-18(IL-18),a cytokine associated with inflammasome activation,in modulating the T-cell response and autoimmune pathogenesis remains largely unclear.In this study,we detected high expression levels of the IL-18 receptorαchain(IL-18Rα)in murine and human Th17 cells.In culture,IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production,a phenotype of pathogenic Th17(pTh17)cells.Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures.Mechanistically,IL-18 promoted Stat3 phosphorylation,which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production.In patients with primary Sjögren’s syndrome(pSS)and systemic lupus erythematosus(SLE),IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity.Moreover,the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren’s syndrome(ESS)model mice and the renal tissues of lupus model mice.Furthermore,adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice,whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice.Together,our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development,indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.
