The mitochondrial gene CMPK2 functions as a rheostat for macrophage homeostasis in inflammation

Abstract

ABSTRACTMitochondria, in addition to cellular energy production, are now being recognized as regulators of the innate immune response of phagocytes. Here we found that down regulation of the mitochondria associated enzyme, Cytidine Monophosphate Kinase 2 (CMPK2), results in a significant de-regulation of resting immune homeostasis of macrophages, presenting as an enhanced expression of the pro-inflammatory genes- IL1β, TNFα and IL8 in these cells associated with enhanced mitochondrial ROS and altered mitochondrial shape. Contrary to expectation, these phenotypic changes were also preserved in cells with constitutive over expression of CMPK2 thereby implicating an important role for this gene in the regulation of inflammatory balance of macrophages. Interestingly, long term modulation of CMPK2 expression resulted in increased glycolytic flux in both the silenced and over-expressing cells akin to the altered physiological state of activated M1 macrophages. While infection induced inflammation for restricting pathogens is regulated, our observation of a total dysregulation of basal inflammation by bidirectional alteration of CMPK2 expression, only highlights a critical role of this gene in mitochondria mediated control of inflammation.