Tpl2^-/- macrophages exhibit impaired mitochondrial respiration due to type I interferon signaling in response to LPS stimulation.

Macrophages are essential to the innate immune system and their dysfunction has been implicated in many diseases, including autoimmunity, obesity, and cancer. Activated macrophages can alter their oxidative phosphorylation, metabolite production, and reactive oxygen species generation to elicit their diverse functions. Tumor progression locus 2 (Tpl2, MAP3K8, or COT) is a serine-threonine kinase involved in macrophage activation and function. In TLR-stimulated macrophages, TPL2 ablation induces high type I interferon (IFN) production. Previous research implicates type I IFNs in metabolic regulation, but their exact mechanism remains unclear. 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, ATP production, and maximal respiration compared to LPS-stimulated wild type and Tpl2^-/-IFNAR^-/- macrophages. LPS-stimulated Tpl2^-/- macrophages had reduced antioxidant gene expression compared to wild type macrophages, including SOD2, HMOX-1, and PRDX5. Disrupted IFN signaling in IFNAR^-/- and Tpl2^-/-IFNAR^-/- macrophages significantly increased antioxidant gene expression, suggesting the absence of IFN signaling mitigates macrophage oxidative stress. These data indicate that Tpl2^-/- macrophages are metabolically defective and type I IFNs contribute to the underlying dysfunction.