Absence of Interleukin‐17 Receptor A Signaling Prevents Autoimmune Inflammation of the Joint and Leads to a Th2‐like Phenotype in Collagen‐Induced Arthritis

Abstract

ObjectiveInterleukin‐17A (IL‐17A) signals through the IL‐17 receptor (IL‐17R) A/C heterodimer. IL‐17RA serves as a common receptor subunit for several IL‐17 cytokine family members. Lack of IL‐17RA signaling may therefore have additional effects beyond those of lack of IL‐17A alone. The present study was undertaken to determine the role of IL‐17RA signaling in autoimmune arthritis.MethodsDisease incidence and severity were scored in type II collagen–treated wild‐type, IL‐17RA–deficient, and IL‐23p19–deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL‐17RA signaling was blocked in vivo in mice with antigen‐induced arthritis (AIA).ResultsComparable to the findings in IL‐23p19–deficient mice, IL‐17RA–deficient mice were completely protected against the development of collagen‐induced arthritis (CIA). However, IL‐17RA–deficient mice exhibited an increased number of IL‐4–producing CD4+ T cells, distinct from IL‐17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL‐17RA–deficient mice had a reduced ability to induce IL‐6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL‐17RA signaling in AIA reduced synovial inflammation.ConclusionThese results demonstrate that absence of IL‐17RA leads to a Th2‐like phenotype characterized by IL‐4 production and suggest that IL‐17RA signaling plays a critical role in the regulation of IL‐4 in CIA and the development of autoimmune inflammation of the joint.