Bone-derived MSCs encapsulated in alginate hydrogel prevent collagen-induced arthritis in mice through the activation of adenosine A_(2A/2B)receptors in tolerogenic dendritic cells

Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,such as rheumatoid arthritis(RA).As multipotent progenitor cells,mesenchymal stem cells(MSCs),can regulate dendritic cells(DCs)to restore their immunosuppressive function and prevent disease development.However,the underlying mechanisms of MSCs in regulating DCs still need to be better defined.Simultaneously,the delivery system for MSCs also influences their function.Herein,MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ,maximizing efficacy in vivo.The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines.In the collagen-induced arthritis(CIA)mice model,alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39^(+)CD73^(+)on MSCs.These enzymes hydrolyze ATP to adenosine and activate A_(2A/2B)receptors on immature DCs,further promoting the phenotypic transformation of DCs to tol DCs and regulating naive T cells to Tregs.Therefore,encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression.This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.

JAK inhibition ameliorated experimental autoimmune encephalomyelitis by blocking GM-CSF-driven inflammatory signature of monocytes

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system(CNS)due to the critical roles of these cells in the production of proinflammatory cytokines,differentiation of T-helper(Th)cells,and antigen presentation.The JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling.However,the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis(MS)is unclear.Here,we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis(EAE),a model for MS.JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6^(Chi)monocytes and monocyte-derived dendritic cells in EAE mice.In parallel,the proportion of GM-CSF^(+)CD4^(+)T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition,which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage.Together,our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.