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Immunity

Immunity

IF: 26.3
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Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

Published:17 July 2025 DOI: 10.1016/j.immuni.2025.06.017
Marco Di Gioia, Valentina Poli, Piao J. Tan, Roberto Spreafico, Anne Chu, Alex G. Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L.S.M. Gordts, Joseph L. Witztum, Talal A. Chatila, Janet Chou, Xu Zhou, James R. Springstead, Ivan Zanoni

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.

Substances (12)

Materials
Procduct Name CAS Molecular Formula Supplier Price
GSK 343 1346704-33-3 C31H39N7O2 177 suppliers $19.00-$2841.00
GSK 343 1346704-33-3 C31H39N7O2 177 suppliers $19.00-$2841.00
GSK 343 1346704-33-3 C31H39N7O2 177 suppliers $19.00-$2841.00
GSK 343 1346704-33-3 C31H39N7O2 177 suppliers $19.00-$2841.00
UNC 1999 1431612-23-5 C33H43N7O2 164 suppliers $14.00-$3876.00
UNC 1999 1431612-23-5 C33H43N7O2 164 suppliers $14.00-$3876.00
UNC 1999 1431612-23-5 C33H43N7O2 164 suppliers $14.00-$3876.00
UNC 1999 1431612-23-5 C33H43N7O2 164 suppliers $14.00-$3876.00
L-Prolinamide, N-[4-[[4-[5-[(2-furanylmethyl)amino]-1,2,4-triazolo[4,3-c]pyrimidin-8-yl]benzoyl]amino]-1-oxobutyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)- 2688842-08-0 C43H48N10O6S 20 suppliers Inquiry
L-Prolinamide, N-[4-[[4-[5-[(2-furanylmethyl)amino]-1,2,4-triazolo[4,3-c]pyrimidin-8-yl]benzoyl]amino]-1-oxobutyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)- 2688842-08-0 C43H48N10O6S 20 suppliers Inquiry

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