Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases.
Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases.
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DOI：
10.1111/imr.12381
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发表时间：
2016-01
影响因子：
8.7
通讯作者：
Buckner JH
中科院分区：
文献类型：
--
作者：
Hamerman JA;Pottle J;Ni M;He Y;Zhang ZY;Buckner JH
toll样受体（TLR）是一种跨膜模式识别受体，可识别巨噬细胞和DC中的微生物配体和炎症细胞因子和I型干扰素的产生信号。虽然tlr诱导的炎症介质是清除病原体所必需的，但许多介质对宿主是有毒的，当过量产生时可引起病理性炎症。tlr诱导的细胞因子在自身免疫性疾病，如类风湿关节炎、炎症性肠病和系统性红斑狼疮中的作用证明了这一点。由于TLR诱导的细胞因子的强大作用，我们有多种机制来抑制TLR信号传导。在这里，我们强调了巨噬细胞和DC中参与TLR反应抑制的三种途径，以及它们在自身免疫中的意义；A20由TNFAIP3基因编码，Lyp由PTPN22基因编码，以及BCAP/PI3K途径。我们提出了新的发现，Lyp促进原代人单核细胞的TLR反应，并且自身免疫风险的Lyp 620w变体比无风险的Lyp 620r更有效地促进TLR诱导的IL-6。这表明Lyp在单核细胞中下调了TLR抑制通路，我们提出Lyp抑制TREM2/DAP12抑制通路。总的来说，这些途径显示了TLR反应的不同负调控机制，并且都影响自身免疫性疾病的发病机制和治疗。
Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and DC. Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced IL-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment.