Journal
SCIENCE SIGNALING
Volume 15, Issue 716, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abi7400
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Funding
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT (MSIT), Republic of Korea [NRF-2018R1A2B2006310, NRF-2021R1H1A2012456, 2021M3A9I2080493]
- Seoul National University Hospital (SNUH) Research Fund [0420210470: 2021-1688]
- National Research Foundation of Korea [2021M3A9I2080493] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Zinc plays a regulatory role in immune responses by affecting signaling pathways in monocytes and macrophages. The concentration of cytoplasmic zinc is determined by the availability of extracellular zinc, which is brought into the cells through the zinc-specific importer Zip8. In inflammatory conditions, the expression of Zip8 is increased, leading to enhanced phosphorylation of S6 kinase through zinc-mediated inhibition of PP2A. This ultimately promotes glycolysis and IL-1 beta production.
The essential micronutrient zinc regulates immune responses by affecting signaling pathways. In activated monocytes and macrophages, signaling networks mediate the metabolic reprogramming that meets the demands of participation in immune responses. Here, we demonstrated that cytoplasmic, bioavailable zinc was essential for promoting IL-1 beta production in activated human monocytes and macrophages downstream of glycolysis induced by the kinase-containing multiprotein complex mTORC1. The concentration of cytoplasmic zinc was determined by that of extracellular zinc, which was brought into cells through the zinc-specific importer Zip8. The abundance of Zip8 was increased in monocytes from patients with rheumatoid arthritis (RA), as well as in LPS-stimulated monocytes and macrophages from healthy individuals. The mTORC1-mediated phosphorylation of S6 kinase (S6K) was enhanced by zinc-mediated inhibition of PP2A, a phosphatase that targets S6K. As a result, IL-1 beta production was increased due to the activation of mTORC1-induced glycolysis. In monocytes of patients with RA, the expression of Zip8 and the zinc-inducible metallothionein isoform MT2A and the phosphorylation of S6K were enhanced compared with those of healthy controls. Furthermore, Zip8 expression correlated with more severe RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic, bioavailable zinc in the metabolic reprogramming of human monocytes and macrophages in inflammatory responses.
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