AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging

Abstract

AMP-activated protein kinase (AMPK) has a crucial role not only in the regulation of tissue energy metabolism but it can also control immune responses through its cooperation with immune signaling pathways, thus affecting immunometabolism and the functions of immune cells. It is known that AMPK signaling inhibits the activity of the NF-κB system and thus suppresses pro-inflammatory responses. Interestingly, AMPK activation can inhibit several major immune signaling pathways, e.g., the JAK-STAT, NF-κB, C/EBPβ, CHOP, and HIF-1α pathways, which induce the expansion and activation of myeloid-derived suppressor cells (MDSC). MDSCs induce an immunosuppressive microenvironment in tumors and thus allow the escape of tumor cells from immune surveillance. Chronic inflammation has a key role in the expansion and activation of MDSCs in both tumors and inflammatory disorders. The numbers of MDSCs also significantly increase during the aging process concurrently with the immunosenescence associated with chronic low-grade inflammation. Increased fatty acid oxidation and lactate produced by aerobic glycolysis are important immunometabolic enhancers of MDSC functions. However, it seems that AMPK signaling regulates the functions of MDSCs in a context-dependent manner. Currently, the activators of AMPK signaling are promising drug candidates for cancer therapy and possibly for the extension of healthspan and lifespan. We will describe in detail the AMPK-mediated regulation of the signaling pathways controlling the expansion and activation of immunosuppressive MDSCs. We will propose that the beneficial effects mediated by AMPK activation, e.g., in cancers and the aging process, could be induced by the inhibition of MDSC functions.