UCLA

Macrophages are innate immune cells that execute a variety of functions including microbial clearance, antigen presentation, and tissue repair. When exposed to the cytokine interleukin 4 (IL-4), these cells express genes associated with alternative activation. Previous work had shown that etomoxir-mediated disruption of coenzyme A homeostasis decreases the macrophage IL-4 response, while exogenous addition of CoA enhances the presence IL-4-associated cell-surface markers. However, the mechanism by which etomoxir decreased intracellular CoA levels and how this ubiquitous metabolic cofactor could instruct alternative activation was entirely unclear. In this work, I show that etomoxir likely decreases intracellular CoA levels by thioester-mediated pantothenate kinase inhibition. Further, I demonstrate that exogenous CoA enhances the IL-4 response in vitro and in vivo. I determined that CoA acts as a weak toll-like receptor 4 agonist, which enhances the IL-4 response through activation of the MyD88 signaling cascade. Finally, I show that activation of the MyD88 pathway is sufficient to enhance alternative activation both in vitro and in vivo.