Autoimmunity. IRF5 mediates joint inflammation.
Autoimmunity. IRF5 mediates joint inflammation.
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DOI：
10.1038/nrrheum.2015.127
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发表时间：
2015-10-01
期刊：
影响因子：
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通讯作者：
Duarte, Joao H
中科院分区：
文献类型：
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作者：
Duarte, Joao H
干扰素调节因子5 （IRF5）是一种参与多种免疫介导机制的转录因子，被认为是关节炎小鼠炎症关节中rna感应toll样受体（TLRs）的致病激活和促炎细胞因子产生之间的新联系。IRF5（编码IRF5的基因）的遗传多态性先前与几种自身免疫性疾病的风险增加有关，包括类风湿性关节炎（RA）。这些发现促使Ian Rifkin和同事研究IRF5在关节炎疾病中的作用；根据Rifkin的说法，“了解IRF5在类风湿性关节炎中的作用可能有助于确定这种疾病发病机制中重要的生物学途径。”通过使用关节炎的K/ bx N血清转移小鼠模型，研究人员发现，与野生型对照相比，Irf5基因敲除（Irf5 - / -）小鼠出现了较轻的关节炎症，这表明踝关节厚度的增加较小，组织学分析得出的疾病评分较低。重要的是，与对照小鼠相比，在关节炎Irf5 - / -小鼠的血清样本中未检测到IL-1β，这表明Irf5在该细胞因子的产生中起重要作用。为了支持这一假设，对关节炎关节mRNA表达的分析发现，与对照组相比，关节炎Irf5 - / -小鼠中caspase-1和cathepsin g这两种参与IL-1加工的蛋白酶表达减少。由于IRF5与TLR反应有关，研究人员还测试了特异性TLR的缺失是否会影响关节炎的发展。虽然TLR2-TLR4双敲除小鼠的疾病至少与对照组一样严重，但缺乏TLR3或TLR7的小鼠的疾病较轻。Rifkin补充说：“由于TLR7和TLR3都是RNA感应tlr，这表明内源性RNA配体可能参与了疾病的发病机制。”此外，与IRF5 - / -小鼠相比，髓细胞特异性缺失IRF5导致的关节炎疾病的严重程度较低，这表明IRF5也作用于非髓细胞，如滑膜成纤维细胞。值得注意的是，在TLR7体外激活后，滑膜成纤维细胞产生的生长调节α蛋白（CXCL1）和IL-6依赖于IRF5。本研究发现IRF5是关节炎症的重要介质，整合TLR信号并指导促炎细胞因子和趋化因子的产生。里夫金和他的同事们现在计划在人类身上证实这些发现，并“将这一分析扩展到观察IRF5在其他免疫和非免疫细胞，特别是滑膜成纤维细胞中的体内作用。”
Interferon regulatory factor 5 (IRF5), a transcription factor involved in several immunemediated mechanisms, was identified as a new link between the pathogenetic activation of RNA-sensing Toll-like receptors (TLRs) and proinflammatory cytokine production in inflamed joints of arthritic mice. Genetic polymorphisms in IRF5 (the gene encoding IRF5) were previously associated with increased risk of several autoimmune diseases, including rheumatoid arthritis (RA). These findings led Ian Rifkin and colleagues to investigate the role of IRF5 in arthritic disease; according to Rifkin,“understanding the role of IRF5 in RA might help identify biological pathways of importance in the pathogenesis of this disease.” By using the K/B× N serum transfer mouse model of arthritis, the researchers found that IRF5-knockout (Irf5–/–) mice developed milder joint inflammation compared with wild-type controls, as shown by a smaller increase in ankle thickness and lower disease scores derived from histological analysis. Importantly, and in contrast to control mice, no IL-1β was detected in serum samples from arthritic Irf5–/–mice, suggesting an important role for IRF5 in the production of this cytokine. Supporting this hypothesis, analysis of mRNA expression in arthritic joints identified caspase-1 and cathepsin G—both proteases involved in IL-1 processing—among the genes with reduced expression in arthritic Irf5–/–mice compared with controls. As IRF5 has been implicated in TLR responses, the researchers also tested whether deletion of specific TLRs affected arthritis development. Whereas disease was at least as severe in TLR2–TLR4 double-knockout mice as in controls, mice deficient for TLR3 or for TLR7 had milder disease.“As TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands are likely to be involved in disease pathogenesis,” adds Rifkin. Furthermore, myeloid-cell-specific deletion of IRF5 led to less severe arthritic disease than in Irf5–/–mice, suggesting that IRF5 also acts in nonmyeloid cells such as synovial fibroblasts. Notably, production of growth-regulated α protein (CXCL1) and IL-6 by synovial fibroblasts after TLR7 activation in vitro was found to be dependent on IRF5. This study identified IRF5 as a crucial mediator of joint inflammation, integrating TLR signals and instructing proinflammatory cytokine and chemokine production. Rifkin and colleagues now plan to confirm these findings in humans and “to extend this analysis to look at the in vivo role of IRF5 in other immune and nonimmune cells, in particular synovial fibroblasts.”