Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan.
Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan.
Life Sci Alliance. 2021 Nov 24;5(2). doi: 10.26508/lsa.202101181. Print 2022 Feb.
TICAM-1 (also called TRIF) is the sole adaptor of TLR3 that recognizes double-stranded RNA. Here, we report that TICAM-1 is involved not only in TLR3 signaling but also in the cytokine receptor IL-17RA signaling. We found that TICAM-1 bound to IL-17R adaptor Act1 to inhibit the interaction between IL-17RA and Act1. Interestingly, knockout promoted IL-17RA/Act1 interaction and increased IL-17A-mediated activation of NF-κB and MAP kinases, leading to enhanced expression of inflammatory cytokines and chemokines upon IL-17A stimulation. Moreover, knockout augmented IL-17A-mediated CXCL1 and CXCL2 expression in vivo, resulting in accumulation of myeloid cells. Furthermore, knockout enhanced delayed type hypersensitivity and exacerbated experimental autoimmune encephalomyelitis. knockout promoted accumulation of myeloid and lymphoid cells in the spinal cord of EAE-induced mice. Collectively, these data indicate that TICAM-1 inhibits the interaction between IL-17RA and Act1 and functions as a negative regulator in IL-17A-mediated inflammatory responses.
TICAM-1（也称为 TRIF）是唯一识别双链 RNA 的 TLR3 衔接蛋白。在这里，我们报告 TICAM-1 不仅参与 TLR3 信号转导，还参与细胞因子受体 IL-17RA 信号转导。我们发现 TICAM-1 与 IL-17R 衔接子 Act1 结合，抑制 IL-17RA 和 Act1 之间的相互作用。有趣的是， 缺失促进了 IL-17RA/Act1 相互作用，并增加了 IL-17A 介导的 NF-κB 和 MAP 激酶的激活，导致在 IL-17A 刺激下炎症细胞因子和趋化因子的表达增强。此外， 缺失增强了体内 IL-17A 介导的 CXCL1 和 CXCL2 的表达，导致髓样细胞的积累。此外， 缺失增强了迟发型超敏反应并加重了实验性自身免疫性脑脊髓炎。 缺失促进了 EAE 诱导的小鼠脊髓中髓样细胞和淋巴样细胞的积累。总之，这些数据表明 TICAM-1 抑制了 IL-17RA 和 Act1 之间的相互作用，并作为 IL-17A 介导的炎症反应的负调节剂发挥作用。
