Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter

Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of...

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Published inbioRxiv : the preprint server for biology
Main Authors Gioia, Marco Di, Poli, Valentina, Tan, Piao J, Spreafico, Roberto, Chu, Anne, Cuenca, Alex G, Gordts, Philip Lsm, Pandolfi, Laura, Meloni, Federica, Witztum, Joseph L, Chou, Janet, Springstead, James R, Zanoni, Ivan
Format Journal Article
LanguageEnglish
Published United States 21.11.2023
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Summary:Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of host-derived factors that participate to inflammation. How these -derived molecules are sensed by macrophages and their impact on immunity remain poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed upon microbial encounter. oxPL blockade restricts inflammation and prevents the death of the host, without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, a master regulator of immunity and metabolism. AKT inhibition potentiates the methionine cycle, and epigenetically dampens , a pluripotent anti-inflammatory cytokine. Overall, we found that host-derived inflammatory cues act as " " virulence factors that initiate ETI and that their activity can be targeted to protect the host against excessive inflammation upon microbial encounter.