Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum-Induced Arthritis
Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum-Induced Arthritis
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DOI：
10.1002/art.38198
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发表时间：
2014-01-01
影响因子：
13.3
通讯作者：
Pope, Richard M.
中科院分区：
文献类型：
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作者：
Huang, Qi-Quan;Birkett, Robert;Pope, Richard M.
目标。Fas信号的非凋亡作用已被认为与炎症和先天免疫的调节有关。本研究旨在阐明巨噬细胞中Fas信号在关节炎发生中的作用。在骨髓系(Cre（LysM)Fas（flox/flox）小鼠）中有条件地删除Fas的小鼠系中诱导K/BxN血清转移性关节炎。对关节炎进行临床和组织学评估。采用酶联免疫吸附法检测白细胞介素-1 β (IL-1 β)、CXCL5、IL-10、IL-6和gp96的表达。骨髓源性巨噬细胞被IL-1 β和gp96激活。流式细胞术分析细胞表型和凋亡情况。Cre(LysM)Fas（flox/flox）小鼠的关节炎发病情况与对照小鼠相当；然而，在慢性期，分解速度加快。减轻的关节炎与内源性toll样受体2 （TLR-2）配体gp96和中性粒细胞趋化趋化因子CXCL5的关节表达降低以及IL-10的表达增强有关。与对照巨噬细胞相比，用IL-1 β或gp96激活fas缺陷小鼠巨噬细胞可诱导IL-10表达增加。IL-10抑制IL-1 β + gp96诱导的IL-6和CXCL5的表达。IL-1 β介导的ERK活化调节IL-10的表达，在fas缺陷小鼠巨噬细胞中升高。综上所述，我们的研究结果表明，Fas信号通路受损导致抗炎IL-10的表达增强，gp96的表达降低，这些作用与关节炎慢性期炎症的加速消退有关。这些观察结果表明，减少内源性TLR配体和增加IL-10的策略可能有益于类风湿关节炎的治疗。
Objective. A nonapoptotic role of Fas signaling has been implicated in the regulation of inflammation and innate immunity. This study was undertaken to elucidate the contribution of Fas signaling in macrophages to the development of arthritis.Methods. K/BxN serum-transfer arthritis was induced in a mouse line in which Fas was conditionally deleted in the myeloid lineage (Cre(LysM)Fas(flox/flox) mice). The arthritis was assessed clinically and histologically. Expression of interleukin-1 beta (IL-1 beta), CXCL5, IL-10, IL-6, and gp96 was determined by enzyme-linked immunosorbent assay. Bone marrow-derived macrophages were activated with IL-1 beta and gp96. Cell phenotype and apoptosis were analyzed by flow cytometry.Results. Arthritis onset in Cre(LysM)Fas(flox/flox) mice was comparable with that observed in control mice; however, resolution was accelerated during the chronic phase. The attenuated arthritis was associated with reduced articular expression of the endogenous Toll-like receptor 2 (TLR-2) ligand gp96 and the neutrophil chemotactic chemokine CXCL5, and enhanced expression of IL-10. Activation with IL-1 beta or gp96 induced increased IL-10 expression in Fas-deficient murine macrophages compared with control macrophages. IL-10 suppressed IL-6 and CXCL5 expression induced by IL-1 beta plus gp96. IL-1 beta-mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient mouse macrophages.Conclusion. Taken together, our findings indicate that impaired Fas signaling results in enhanced expression of antiinflammatory IL-10 and reduced expression of gp96, and these effects are associated with accelerated resolution of inflammation during the chronic phase of arthritis. These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in the treatment of rheumatoid arthritis.