Itaconate-mediated regulation of innate immunity during fungal pneumonia 3275

Abstract Description Innate responses to pathogens often involve metabolic reprogramming via disruption of the Krebs cycle leading to the accumulation of various metabolites that can further influence innate cell responses during infection. One such metabolite is itaconate, which is produced when cis-aconitate is decarboxylated via aconitate decarboxylase 1. In the current report, we demonstrate that mice deficient in aconitate decarboxylase 1 (Acod1), and therefore deficient in itaconate, are more resistant to A. fumigatus fungal pneumonia. The reduction in fungal burden in the absence of itaconate correlated with increased production of pro-inflammatory cytokines known to be required for A. fumigatus clearance, namely IL-17A and IL-22. Although alveolar macrophages and neutrophils were not increased in the lungs of A. fumigatus-challenged Acod1-/- mice, these innate immune cell types demonstrated enhanced antifungal activity against A. fumigatus. Furthermore, we show that culturing murine alveolar macrophages with excess itaconate resulted in a diminished killing capacity. These findings were replicated in cultures of human monocyte-derived macrophages cultured with excess itaconate, indicating that our observations were not specific to one species nor to one macrophage subset. Collectively, these data indicate an immune regulatory role for itaconate and a potential therapeutic target to enhance protection from A. fumigatus. Funding Sources NIH R01 HL122426 NIH R01 HL136211 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)