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The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Miyamoto, K;Sujino, T;Harada, Y;Ashida, H;Yoshimatsu, Y;Yonemoto, Y;Nemoto, Y;Tomura, M;Melhem, H;Niess, JH;Suzuki, T;Suzuki, T;Suzuki, S;Koda, Y;Okamoto, R;Mikami, Y;Teratani, T;Tanaka, K;Yoshimura, A;Sato, T;Kanai, T;

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.