Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands.
Department of Experimental Immunology, Amsterdam UMC, Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2019 Apr 8;10:739. doi: 10.3389/fimmu.2019.00739. eCollection 2019.
Antigen-presenting cells (APCs) such as dendritic cells (DCs) are crucial for initiation of adequate inflammatory responses, which critically depends on the cooperated engagement of different receptors. In addition to pattern recognition receptors (PRRs), Fc gamma receptors (FcγRs) have recently been identified to be important in induction of inflammation by DCs. FcγRs that recognize IgG immune complexes, which are formed upon opsonization of pathogens, induce pro-inflammatory cytokine production through cross-talk with PRRs such as Toll-like receptors (TLRs). While the physiological function of FcγR-TLR cross-talk is to provide protective immunity against invading pathogens, undesired activation of FcγR-TLR cross-talk, e.g., by autoantibodies, also plays a major role in the development of chronic inflammatory disorders such as rheumatoid arthritis (RA). Yet, the molecular mechanisms of FcγR-TLR cross-talk are still largely unknown. Here, we identified that FcγR-TLR cross-talk-induced cytokine production critically depends on activation of the transcription factor interferon regulatory factor 5 (IRF5), which results from induction of two different pathways that converge on IRF5 activation. First, TLR stimulation induced phosphorylation of TBK1/IKKε, which is required for IRF5 phosphorylation and subsequent activation. Second, FcγR stimulation induced nuclear translocation of IRF5, which is essential for gene transcription by IRF5. We identified that IRF5 activation by FcγR-TLR cross-talk amplifies pro-inflammatory cytokine production by increasing cytokine gene transcription, but also by synergistically inducing glycolytic reprogramming, which is another essential process for induction of inflammatory responses by DCs. Combined, here we identified IRF5 as a pivotal component of FcγR-TLR cross-talk in human APCs. These data may provide new potential targets to suppress chronic inflammation in autoantibody-associated diseases that are characterized by undesired or excessive FcγR-TLR cross-talk, such as RA, systemic sclerosis, and systemic lupus erythematous.
抗原呈递细胞（APCs），如树突状细胞（DCs），对于启动充分的炎症反应至关重要，而这严重依赖于不同受体的协同结合。除了模式识别受体（PRRs）外，Fcγ 受体（FcγRs）最近也被确定为 DC 诱导炎症的重要因素。FcγRs 识别 IgG 免疫复合物，当病原体被调理时就会形成免疫复合物，通过与 Toll 样受体（TLRs）等 PRRs 的交联来诱导促炎细胞因子的产生。虽然 FcγR-TLR 交联的生理功能是提供针对入侵病原体的保护性免疫，但 FcγR-TLR 交联的不当激活，例如自身抗体的激活，也在类风湿关节炎（RA）等慢性炎症性疾病的发展中起主要作用。然而，FcγR-TLR 交联的分子机制在很大程度上仍不清楚。在这里，我们发现 FcγR-TLR 交联诱导的细胞因子产生严重依赖于转录因子干扰素调节因子 5（IRF5）的激活，而这是由两条不同途径的诱导汇聚于 IRF5 激活而产生的。首先，TLR 刺激诱导 TBK1/IKKε 的磷酸化，这是 IRF5 磷酸化和随后激活所必需的。其次，FcγR 刺激诱导 IRF5 的核转位，这对于 IRF5 基因转录是必需的。我们发现，FcγR-TLR 交联诱导的 IRF5 激活通过增加细胞因子基因转录来放大促炎细胞因子的产生，同时通过协同诱导糖酵解重编程来放大促炎细胞因子的产生，这也是 DC 诱导炎症反应的另一个重要过程。综上所述，我们发现 IRF5 是人类 APCs 中 FcγR-TLR 交联的关键组成部分。这些数据可能为抑制自身抗体相关疾病中的慢性炎症提供新的潜在靶点，这些疾病的特征是 FcγR-TLR 交联不当或过度，如 RA、系统性硬化症和系统性红斑狼疮。
