Bacterial infection induces asthma resistance by promoting macrophage efferocytosis via ACOD1-itaconate-SHP2 axis 2398

Abstract Description Asthma is a refractory disease with great variety in incidence based on environmental differences. The hygiene hypothesis suggests that recurrent bacterial infections reduce the incidence of asthma. However, the underline mechanism remains incompletely understood. Using RNA sequencing, we found aconitate decarboxylase 1 (ACOD1) was up-regulated in macrophages in a Staphylococcus aureus-induced house dust mite-originated asthma resistance animal model. ACOD1 deficient mice and macrophage adoptive transfer showed the disappearance of asthma resistance and a significant increase in asthmatic inflammation, airway hyperreactivity and a decrease in macrophage efferocytosis. Mechanistically, itaconate, the immune metabolite derived from ACOD1, alkylated Cys174 of SH2 domain containing protein tyrosine phosphatase-2 (SHP2), inhibiting its binding to macrophage efferocytosis receptor Axl, and promoting macrophage efferocytosis. Taken together, our study suggests that bacterial infection induces metabolic reprogramming, enhancing macrophage efferocytosis and asthma resistance through ACOD1-itaconate-SHP2 axis. Funding Sources This work was supported by National Natural Science Foundation of China 82473928, 82404636, 82273934, and 82373875. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)