AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling

AMPK attenuates CD40-mediated inflammatory activity in myeloid APC; its activity in both APC and T cells contributes to T cell functional polarization. AMPK is a serine/threonine kinase that regulates energy homeostasis and metabolic stress in eukaryotes. Previous work from our laboratory, as well as by others, has provided evidence that AMPK1 acts as a negative regulator of TLR-induced inflammatory function. Herein, we demonstrate that AMPK1-deficient macrophages and DCs exhibit heightened inflammatory function and an enhanced capacity for antigen presentation favoring the promotion of Th1 and Th17 responses. Macrophages and DCs generated from AMPK1-deficient mice produced higher levels of proinflammatory cytokines and decreased production of the anti-inflammatory cytokine IL-10 in response to TLR and CD40 stimulation as compared with WT cells. In assays of antigen presentation, AMPK1 deficiency in the myeloid APC and T cell populations contributed to enhanced IL-17 and IFN- production. Focusing on the CD154-CD40 interaction, we found that CD40 stimulation resulted in increased phosphorylation of ERK1/2, p38, and NF-B p65 and decreased activation of the anti-inflammatory Akt -GSK3-CREB pathway in DCs deficient for AMPK1. Our data demonstrate that AMPK1 serves to attenuate LPS and CD40-mediated proinflammatory activity of myeloid APCs and that AMPK1 activity in both APC and T cells contributes to T cell functional polarization during antigen presentation.