Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

Marco Di Gioia¹, Valentina Poli¹, Piao J Tan², Roberto Spreafico³, Anne Chu¹, Alex G Cuenca⁴, Zhongyang Wu⁵, Mehdi Benamar¹, Laura Pandolfi⁶, Federica Meloni⁶, Fatemeh Askarian⁷, Jason Hsiao⁸, Elizaveata Borroum⁸, Victor Nizet⁷, Philip L S M Gordts⁹, Joseph L Witztum¹⁰, Talal A Chatila¹, Janet Chou¹, Xu Zhou⁵, James R Springstead², Ivan Zanoni¹¹

Affiliations

¹ Harvard Medical School and Boston Children's Hospital, Division of Immunology, Boston, MA, USA.
² Department of Chemical and Paper Engineering, Western Michigan University, Kalamazoo, MI, USA.
³ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Surgery, Boston Children's Hospital, Boston, MA, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁵ Harvard Medical School and Boston Children's Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, MA, USA.
⁶ Respiratory Disease Unit IRCCS San Matteo Hospital Foundation, and Department of Internal Medicine and Pharmacology, University of Pavia, Pavia, Italy.
⁷ Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
⁸ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
⁹ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, Division of Microbiology and Immunology, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
¹⁰ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹¹ Harvard Medical School and Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Harvard Medical School and Boston Children's Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, MA, USA. Electronic address: ivan.zanoni@childrens.harvard.edu.

PMID: 40680750
PMCID: PMC12313134 (available on 2026-07-17)
DOI: 10.1016/j.immuni.2025.06.017

Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

Marco Di Gioia et al. Immunity. 2025.

. 2025 Sep 9;58(9):2190-2207.e13.

doi: 10.1016/j.immuni.2025.06.017. Epub 2025 Jul 17.

Authors

Affiliations

¹ Harvard Medical School and Boston Children's Hospital, Division of Immunology, Boston, MA, USA.
² Department of Chemical and Paper Engineering, Western Michigan University, Kalamazoo, MI, USA.
³ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Surgery, Boston Children's Hospital, Boston, MA, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁵ Harvard Medical School and Boston Children's Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, MA, USA.
⁶ Respiratory Disease Unit IRCCS San Matteo Hospital Foundation, and Department of Internal Medicine and Pharmacology, University of Pavia, Pavia, Italy.
⁷ Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
⁸ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
⁹ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, Division of Microbiology and Immunology, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
¹⁰ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹¹ Harvard Medical School and Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Harvard Medical School and Boston Children's Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, MA, USA. Electronic address: ivan.zanoni@childrens.harvard.edu.

PMID: 40680750
PMCID: PMC12313134 (available on 2026-07-17)
DOI: 10.1016/j.immuni.2025.06.017

Abstract

Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.

Keywords: ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

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Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

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