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 language | English |
|---|---|
| Pages (from-to) | 2077-2094.e12 |
| Journal | Immunity |
| Volume | 57 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 10 2024 |
Bibliographical note
Publisher Copyright:© 2024 Elsevier Inc.
Funding
We thank Drs. Jonathan Kagan, Francisco Quintana, Ruaidhri Jackson, Katie Galloway, and Charles Jennings for their support, helpful discussion, and critique of this manuscript. We thank the Bauer Sequencing Core at Harvard Medical School for assisting with snATAC-seq experiments. We thank the NeuroTechnology Studio at Brigham and Women's Hospital for providing Seahorse instrument access, and Andrew Lee for computational analysis. This work was supported by grants made available to R.N. by the Crohn's and Colitis Foundation, NIH (R35GM133800), and the Kenneth Rainin Foundation. A.M. was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate (NDSEG) Fellowship Program. M.H. was supported by funding from the Evergrande Center for Immunologic Diseases. S.B. and I.L. were supported by the National Research Foundation of Korea (MSIT 2019M3A9B6065192). This article is subject to HHMI's Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. Conceptualization and design of the project \u2013 R.T.M. A.M. and R.N.; experimentation and data analysis \u2013 R.T.M. A.M. P.X. S.B. J.M.R. K.N.S. B.P. J.R.B. D.M. A.S.A. S.G.A. N.K, M.H. and R.N.; computational methodology and analysis \u2013 S.B. I.L. and M.H.; Mathematical modeling \u2013 A.M.; provision of key resources \u2013 G.-P.S. R.A.F. A.C.A. N.K. M.H. and R.N.; funding and supervision of the project \u2013 R.N.; writing the manuscript \u2013 R.T.M. A.M. and R.N.; editing the manuscript \u2013 R.T.M. A.M. J.M.R. D.M. S.G.A. A.C.A. M.H. N.K. and R.N. The authors declare no competing financial interests. We thank Drs. Jonathan Kagan, Francisco Quintana, Ruaidhri Jackson, Katie Galloway, and Charles Jennings for their support, helpful discussion, and critique of this manuscript. We thank the Bauer Sequencing Core at Harvard Medical School for assisting with snATAC-seq experiments. We thank the NeuroTechnology Studio at Brigham and Women\u2019s Hospital for providing Seahorse instrument access, and Andrew Lee for computational analysis. This work was supported by grants made available to R.N. by the Crohn's and Colitis Foundation , NIH ( R35GM133800 ), and the Kenneth Rainin Foundation . A.M. was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate (NDSEG) Fellowship Program. M.H. was supported by funding from the Evergrande Center for Immunologic Diseases . S.B. and I.L. were supported by the National Research Foundation of Korea ( MSIT 2019M3A9B6065192 ). This article is subject to HHMI\u2019s Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication.
| Funders | Funder number |
|---|---|
| National Research Foundation of Korea | |
| National Defense Science and Engineering Graduate | |
| Crohn's and Colitis Foundation of America | |
| Evergrande Center for Immunologic Diseases | |
| Kenneth Rainin Foundation | |
| U.S. Department of Defense | |
| Howard Hughes Medical Institute | |
| National Institutes of Health (NIH) | R35GM133800 |
| MSIT | 2019M3A9B6065192 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
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
Fingerprint
Dive into the research topics of 'A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver