Absence of Interleukin-17 Receptor A Signaling Prevents Autoimmune Inflammation of the Joint and Leads to a Th2-like Phenotype in Collagen-Induced Arthritis
Absence of Interleukin-17 Receptor A Signaling Prevents Autoimmune Inflammation of the Joint and Leads to a Th2-like Phenotype in Collagen-Induced Arthritis
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DOI：
10.1002/art.38229
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发表时间：
2014-02-01
影响因子：
13.3
通讯作者：
Lubberts, Erik
中科院分区：
文献类型：
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作者：
Corneth, Odilia B. J.;Mus, Adriana M. C.;Lubberts, Erik
Objective.白细胞介素-17 A（IL-17 A）通过IL-17受体（IL-17 R）A/C异源二聚体发出信号。IL-17 RA作为几种IL-17细胞因子家族成员的共同受体亚基。因此，缺乏IL-17 RA信号传导可能具有超出单独缺乏IL-17 A的那些的额外作用。本研究旨在确定IL-17 RA信号在自身免疫性关节炎中的作用。在II型胶原处理的野生型、IL-17 RA缺陷型和IL-23 p19缺陷型小鼠中对疾病发病率和严重程度进行评分。在几个时间点分析了辅助性T细胞谱和体液免疫反应。通过体外功能测定确定T细胞和总脾细胞的致病性。IL-17 RA信号在抗原诱导的关节炎（AIA）小鼠体内被阻断。与IL-23 p19缺陷小鼠的发现相比，IL-17 RA缺陷小鼠完全免受胶原诱导的关节炎（CIA）的发展。然而，IL-17 RA缺陷型小鼠表现出IL-4产生性CD 4 + T细胞数量增加，这与IL-17 A + CD 4 + T细胞不同。这与较少的浆细胞、较低的致病性IgG 2c抗体产生和增加的IgG 1抗体产生有关。在功能性体外试验中，来自IL-17 RA缺陷小鼠的分离的CD 4 + T细胞和总脾细胞在CIA的情况下诱导滑膜成纤维细胞产生IL-6的能力降低。此外，阻断AIA中IL-17 RA信号转导可减轻滑膜炎症。这些结果表明，IL-17 RA的缺乏导致以IL-4产生为特征的Th 2样表型，并表明IL-17 RA信号传导在CIA中IL-4的调节和关节自身免疫炎症的发展中起关键作用。
Objective. Interleukin-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.Methods. Disease 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).Results. Comparable 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.Conclusion. These 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.