4-Hydroxynonenal suppresses IL-10 production during infection

Sepsis is a syndrome of life-threatening multiple organ failure induced by infection and hallmarked by the increased production of inflammatory cytokines and reactive oxygen species (ROS). The oxidation of lipids by ROS produces 4-hydroxynonenal (4-HNE), a highly reactive aldehyde that forms adducts with proteins and thereby impacts immune signaling. In this study, using blood samples from patients with sepsis at the emergency department, collected by the Acutelines data- and biobank, we show that 4-HNE selectively suppresses the production of the anti-inflammatory cytokine interleukin (IL)-10, while pro-inflammatory IL-6 and tumor necrosis factor (TNF)-α are unaffected. Mechanistically, 4-HNE causes a pronounced transcriptional reorganization, leading to metabolic reprogramming and activation of HIF-1α signaling. In turn, this suppresses IL-10 production through inhibition of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) signaling, whereas IL-6 and TNF-α are unaffected due to increased activation of p38 mitogen-activated protein kinase (MAPK) signaling. This suppression likely occurs in sepsis, because, whereas overall 4-HNE protein adduct levels are increased in blood samples of sepsis patients, they are decreased in monocytes and T cells and negatively correlate with IL-10 levels. Thus, our data show that 4-HNE selectively suppresses IL-10 production in sepsis. This is likely relevant to the clinical outcome of sepsis patients because IL-10 levels correlate with mortality.