TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor–mediated inflammatory responses

• Published in: Life science alliance Vol. 5; no. 2; p. e202101181
• Main Authors: Miyashita, Yusuke, Kouwaki, Takahisa, Tsukamoto, Hirotake, Okamoto, Masaaki, Nakamura, Kimitoshi, Oshiumi, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance LLC 01.02.2022
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Autoimmune Diseases - etiology; Autoimmune Diseases - metabolism; Autoimmunity; Biomarkers; Connexin 43 - metabolism; Disease Susceptibility; Gene Knockdown Techniques; Inflammation - etiology; Inflammation - metabolism; Mice; Peptide Fragments - metabolism; Receptors, Interleukin - metabolism; Signal Transduction
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202101181

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, TICAM-1 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, Ticam-1 knockout augmented IL-17A–mediated CXCL1 and CXCL2 expression in vivo, resulting in accumulation of myeloid cells. Furthermore, Ticam-1 knockout enhanced delayed type hypersensitivity and exacerbated experimental autoimmune encephalomyelitis. Ticam-1 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.