Tpl2−/− macrophages exhibit impaired mitochondrial respiration and function in response to LPS stimulation.

Abstract

Abstract Macrophages are instrumental in maintaining immune homeostasis, and their dysfunction or depletion is tied to many human diseases, including autoimmunity, obesity, and cancer. Activated macrophages modify their cellular metabolic pathways, such as glycolysis and oxidative phosphorylation, to drive their diverse functions. Many metabolic processes occur in the mitochondria, including oxidative phosphorylation, metabolite production, and reactive oxygen species (ROS) generation. Previous research demonstrated that tumor progression locus 2 (Tpl2, MAP3K8, or COT) is required for the induction of oxidative phosphorylation and the alternatively activated phenotype in macrophages during Schistosome infection; however, Tpl2 regulation of cellular metabolism in classically activated macrophages remains unexplored. We hypothesize that Tpl2 normally promotes oxidative phosphorylation, and its absence causes mitochondrial dysfunction. LPS-stimulated Tpl2−/−bone marrow-derived macrophages (BMDMs) had decreased oxygen consumption, basal respiration, ATP production, and maximal respiration compared to LPS-stimulated wild type BMDMs. Additionally, Tpl2−/−BMDMs exhibited higher basal and LPS-stimulated ROS production than wild type BMDMs. These data suggest that Tpl2−/−mitochondria are functionally defective, and the absence of TPL2 increases mitochondrial oxidative stress. Together, this may reveal the underlying mechanism for defective Tpl2−/−macrophage behavior. Understanding the role of Tpl2 in classically activated macrophages will provide a foundation for developing targeted therapies to treat cancer and autoimmune diseases. Supported by grant from NIH (R21 AI147003).