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Updated: Sep 14, 2025

Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
Published on: September 13, 2024
Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response
Marco Di Gioia1, Valentina Poli1, Piao J Tan2
1Harvard Medical School and Boston Children's Hospital, Division of Immunology, Boston, MA, USA.
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.
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