Cytoplasmic labile zinc regulates IL-1β production in human monocytes/macrophages via mTORC1-induced glycolysis

Abstract

Abstract Zinc is an essential micronutrient that plays critical roles in multiple facets of biological processes, including growth, development, proliferation, and differentiation. Since dysregulated zinc homeostasis impairs overall immune function and resultantly, increases susceptibility to infection, much attention has been recently paid to immunomodulatory roles of zinc in immune cells. Rapid and efficient production of proinflammatory cytokines, such as IL-1β and TNF-α, is a primary effect function of monocytes/macrophages for host defense. However, the molecular mechanism involved with zinc-mediated modulation of cytokine production in monocytes/macrophages needs to be better understood. In present study, we provide evidence that cytoplasmic labile zinc is essential for modulation of IL-1β production in human monocytes/macrophages via mTORC1-induced glycolysis. We found that cytoplasmic level of labile zinc in human monocytes/macrophages was largely influenced by extracellular zinc concentrations, possibly via zinc importers such as ZIP1- and ZIP8-mediated influx. The phosphorylation of S6 kinase, a substrate of mTORC1, was significantly enhanced by zinc-mediated inhibition of PP2A, a phosphatase contracting S6K phosphorylation and consequently, IL-1β production was increased by activated mTORC1-induced glycolysis. These results provide new insight how labile zinc modulate a production of cytokines by metabolic reprograming in human monocytes/macrophages.