Tpl2-/- macrophages exhibit impaired mitochondrial function in response to type I interferon signaling in response to LPS stimulation 9396

Abstract Description Macrophages are crucial to the innate immune system and their dysfunction has been implicated in many diseases, including autoimmunity, cancer, and obesity. Activated macrophages can alter their oxidative phosphorylation, reactive oxygen species (ROS) generation, and antioxidant production to elicit their diverse functions. Tumor progression locus 2 (TPL2, MAP3K8, or COT) is a serine-threonine kinase involved in macrophage activation and its ablation induces high type I interferon (IFN) production upon stimulation. Previous research has implicated type I IFNs in metabolic regulation, but their exact mechanism remains unclear in pro-inflammatory macrophages. We hypothesize that TPL2 promotes oxidative phosphorylation in LPS-stimulated macrophages by suppressing type I IFN signaling. LPS-stimulated Tpl2-/- bone marrow-derived macrophages had decreased oxygen consumption compared to LPS-stimulated wild type and Tpl2-/-IFNAR-/- macrophages. Tpl2-/- macrophages had reduced mitochondrial complex II activity and ROS production suggesting high type I IFNs decreased macrophage mitochondrial function. This resulted in LPS-stimulated Tpl2-/- macrophages having reduced SOD2, HMOX-1, and PRDX5 antioxidant gene expression relative to wild type, IFNAR-/-, and Tpl2-/-IFNAR-/- macrophages. These data indicate that Tpl2-/- macrophages are metabolically defective and their elevated type I IFN production contributes to their impaired mitochondria in a pro-inflammatory environment. Funding Sources Supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378 and TL1TR002382. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)