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Nociceptor-derived Reg3γ prevents endotoxic death by targeting kynurenine pathway in microglia

Erika Sugisawa1, Takeshi Kondo2, Yutaro Kumagai3

  • 1WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.

Cell Reports
|March 9, 2022
PubMed

Insights

Nociceptors release the hormone Reg3γ, protecting against endotoxic death by regulating brain metabolism. This discovery offers new insights into immune tolerance during sepsis.

Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Nociceptors modulate immunity, but their role in endotoxic death is unclear.
  • Mechanisms linking nociception to systemic inflammation require elucidation.

Purpose of the Study:

  • Identify novel nociceptor-derived factors involved in endotoxic death.
  • Elucidate the role of Reg3γ in host defense during endotoxemia.

Main Methods:

  • Utilized mouse models of endotoxemia (LPS administration).
  • Investigated nociceptor-null and Reg3γ-deficient mice.
  • Analyzed microglial gene expression, brain metabolism (ATP production, HK1 phosphorylation), and kynurenine pathway metabolites.
  • Examined the effect of central Reg3γ administration.

Main Results:

  • Nociceptor-derived Reg3γ protects against endotoxic death.
  • Reg3γ suppresses microglial indoleamine dioxygenase 1 (IDO1) via the Extl3-Bcl10 axis.
  • Nociceptor-null and Reg3γ-deficient mice show increased mortality, reduced brain ATP, and suppressed HK1 phosphorylation.
  • Brain quinolinic acid accumulation contributes to metabolic dysfunction.

Conclusions:

  • Nociceptor-derived Reg3γ acts as a hormone targeting brain microglia.
  • Reg3γ enhances brain ATP production and protects against endotoxic shock.
  • This study reveals a novel neuro-immune axis in sepsis tolerance.
Keywords:
Reg3gkynurenine pathwaymicroglianociceptor

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