Cell-type Specific Role Of P38? Signaling Pathway In The Pathogenesis Of Rheumatoid Arthritis

Rheumatoid arthritis?RA?is the most common chronic autoimmune disease,characterized by persistent inflammation of the joints,leading to cartilage and bone damage,disability and eventually enhancing morbidity and mortality.Although the etiology of RA remains elusive,the involvement of type 17 T-helper?Th17?cells appears to be pivotal and inhibition of Th17 differentiation and function might be an effective strategy for the treatment of RA.While the involvement of T cell-intrinsic pathways has been described abundantly,it is largely unexplored how Th17 cell development and Th17-depedent RA is triggered by extrinsic pathways.The differentiation of Th17 cells depends on innate signals provided by antigen presenting cell?APC?.Dendritic cells?DCs?is one of the most important APCs,but how does DCs use the cellular signaling pathway to regulate Th17 differentiation and function once upon stimulation is still not well known.The mitogen-activated protein kinase?MAPK?signaling pathway is one of the key pathways for DCs to respond to extracellular signals and regulate the inflammatory responses,including p38?,JNK and ERK.Among them,p38? MAPK is the most crucial regulator of immune response,but the role of p38? in the regulation of RA pathogenesis is still elusive.In this study,we explored the role of p38? in DCs in the pathogenesis of CFA/CII induced arthritis by using mice with p38? specific deletion in DCs.The results showed that defficiency of p38? in DCs could significantly reduce the incidence and disease severity of arthritis in mice,along with decreased Th17 cells.Mechanistic study showed that the antigen degradation ability of p38?-deficient DCs was impaired.Moreover,the percentages of migratory p38?-deficient DCs in the draining lymph node were greatly decreased due to the migratory defect in these DCs.In p38?-deficient DCs,the TAK1-MKK4/7-JNK-c-Jun axis was hyper-activated and IL-27 levels were upregulated,which sequentially suppressed Th17 diffirentiation.We next analyzed the effect of Th17/IL-17 on the fibroblast-like synoviocyte?FLS?.P38 activity in FLS was greatly increased upon IL-17 stimulation.Inhibition of p38? could promote the apoptosis of FLS,but suppress its proliferation and migration.In addition,inhibition of p38? largely reduced the expression of certain IL-17-stimulated chemokines and cytokines through modulating the p38?-MK2 axis.To determine the role of p38? in DCs in antibody induced RA,we leveraged the K/Bx N serum-induced mouse arthritis model.The results showed that p38?^?DC mice had less swelling joints,lower concentration of autoantibodies and decreased percentages of Tfh and GC B cells than WT mice,indicating that DCs p38? could promote the autoantiboy-induced joint destruction.To evaluate p38? as a potential therapeutic target for the treatment of RA,we examined whether inhibition of p38? activity can alleviate RA inflammation.We acutely ablated p38? expression after the second immunization and we found that this treatment could greatly suppress the expression of IL-17-related cytokines and the production of autoantibodies,as well as reduced the incidence and severity of arthritis.Collectively,our findings indicate a critical role for DCs and FLS p38? signaling in the regulation of inflammatory responses during RA development and suggest that targeting p38? signaling may offer an effective therapeutic approach to treat RA.