Nociceptor-derived Reg3γ prevents endotoxic death by targeting kynurenine pathway in microglia
Erika Sugisawa,
Takeshi Kondo,
Yutaro Kumagai,
Hiroki Kato,
Yasunori Takayama,
Kayako Isohashi,
Eku Shimosegawa,
Naoki Takemura,
Yoshinori Hayashi,
Takuya Sasaki,
Mikaël M. Martino,
Makoto Tominaga,
Kenta Maruyama
Affiliations
Erika Sugisawa
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Takeshi Kondo
Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido 060-8636, Japan
Yutaro Kumagai
Biotechnology Research Institute for Drug Discovery, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8565, Japan
Hiroki Kato
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Yasunori Takayama
Department of Physiology, Showa University School of Medicine, Showa University, Tokyo 142-8555, Japan
Kayako Isohashi
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Eku Shimosegawa
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Naoki Takemura
Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
Yoshinori Hayashi
Department of Physiology, School of Dentistry, Nihon University, Tokyo 101-8310, Japan
Takuya Sasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
Mikaël M. Martino
European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia
Makoto Tominaga
National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8787, Japan
Kenta Maruyama
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan; National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8787, Japan; Corresponding author
Summary: Nociceptors can fine-tune local or systemic immunity, but the mechanisms of nociceptive modulation in endotoxic death remain largely unknown. Here, we identified C-type lectin Reg3γ as a nociceptor-enriched hormone that protects the host from endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates the brain and suppresses the expression of microglial indoleamine dioxygenase 1, a critical enzyme of the kynurenine pathway, via the Extl3-Bcl10 axis. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by decreased brain HK1 phosphorylation and ATP production despite normal peripheral inflammation. Such metabolic arrest is only observed in the brain, and aberrant production of brain quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, causes HK1 suppression. Strikingly, the central administration of Reg3γ protects mice from endotoxic death by enhancing brain ATP production. By identifying nociceptor-derived Reg3γ as a microglia-targeted hormone, this study provides insights into the understanding of tolerance to endotoxic death.
