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

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 release of host-derived damage-associated molecular patterns, contributing to shape immunity. How self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter. We show that oxPLs exacerbate inflammation without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, potentiating the methionine cycle and the activity of the epigenetic writer enhancer of zeste homolog 2 (EZH2). EZH2 epigenetically dampens the pluripotent anti-inflammatory cytokine interleukin-10, contributing to death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental anti-microbial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.