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

doi:10.1016/j.immuni.2024.06.001

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

Immunity. 2024 Sep 10;57(9):2077-2094.e12. doi: 10.1016/j.immuni.2024.06.001. Epub 2024 Jun 20.

Authors

Randall T Mertens¹, Aditya Misra², Peng Xiao³, Seungbyn Baek⁴, Joseph M Rone¹, Davide Mangani³, Kisha N Sivanathan¹, Adedamola S Arojojoye⁵, Samuel G Awuah⁶, Insuk Lee⁷, Guo-Ping Shi⁸, Boryana Petrova⁹, Jeannette R Brook⁹, Ana C Anderson¹⁰, Richard A Flavell¹¹, Naama Kanarek¹², Martin Hemberg¹³, Roni Nowarski¹⁴

Affiliations

¹ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
² Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
⁵ Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
⁶ Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
⁷ Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; POSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.
⁸ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.
¹² Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: rnowarski@bwh.harvard.edu.

PMID: 38906145
DOI: 10.1016/j.immuni.2024.06.001

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.

Keywords: IL-18; SLC12A3; bistable circuit; cGAMP; fatty acid oxidation; immunometabolism; intestinal tolerance; macrophage; metabolic reprogramming; metabolic switch.

MeSH terms

Animals
Fatty Acids / metabolism
Glycolysis
Humans
Immune Tolerance*
Immunity, Innate
Inflammation / immunology
Inflammation / metabolism
Interleukin-18* / immunology
Interleukin-18* / metabolism
Intestinal Mucosa / immunology
Intestinal Mucosa / metabolism
Intestines / immunology
Macrophages* / immunology
Macrophages* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nucleotides, Cyclic* / metabolism
Oxidation-Reduction

Substances

Interleukin-18
Nucleotides, Cyclic
cyclic guanosine monophosphate-adenosine monophosphate
Fatty Acids