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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number110462
JournalCell Reports
Issue number10
Publication statusPublished - 2022 Mar 8
Externally publishedYes


  • Reg3g
  • kynurenine pathway
  • microglia
  • nociceptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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