A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance

Randall T. Mertens, Aditya Misra, Peng Xiao, Seungbyn Baek, Joseph M. Rone, Davide Mangani, Kisha N. Sivanathan, Adedamola S. Arojojoye, Samuel G. Awuah, Insuk Lee, Guo Ping Shi, Boryana Petrova, Jeannette R. Brook, Ana C. Anderson, Richard A. Flavell, Naama Kanarek, Martin Hemberg, Roni Nowarski

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2′3′-cyclic GMP–AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.

Original languageEnglish
Pages (from-to)2077-2094.e12
JournalImmunity
Volume57
Issue number9
DOIs
StatePublished - Sep 10 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

Keywords

  • IL-18
  • SLC12A3
  • bistable circuit
  • cGAMP
  • fatty acid oxidation
  • immunometabolism
  • intestinal tolerance
  • macrophage
  • metabolic reprogramming
  • metabolic switch

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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