Cytoplasmic zinc promotes IL-1β production by monocytes and macrophages through mTORC1-induced glycolysis in rheumatoid arthritis

Zinc metabolically reprograms monocytes and macrophages to promote inflammation in rheumatoid arthritis.

Arthritis

1/17/2022 10:00:00 AM

Zinc is an essential micronutrient, but new cell experiments in SciSignal show that zinc influx into immune cells can “reprogram” them into a form that exacerbates inflammation in rheumatoid arthritis.

Zinc metabolically reprograms monocytes and macrophages to promote inflammation in rheumatoid arthritis.

Amplifying rheumatoid arthritisInflammation requires metabolic reprogramming of monocytes and macrophages to support immune responses, such as the synthesis of the proinflammatory cytokine IL-1β. Kimet al.showed that intracellular zinc ions promoted a metabolic shift in human monocytes and macrophages that enhanced IL-1β production. Zinc influx into monocytes and macrophages required the expression of the gene encoding the transporter Zip8. The authors identified the signaling pathway that was activated by zinc and that promoted the shift to glycolytic metabolism that was required for increased IL-1β production. In monocytes from rheumatoid arthritis patients, plasma zinc concentrations and

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REFERENCES AND NOTES Amplifying rheumatoid arthritis Inflammation requires metabolic reprogramming of monocytes and macrophages to support immune responses, such as the synthesis of the proinflammatory cytokine IL-1β. Kim et al. showed that intracellular zinc ions promoted a metabolic shift in human monocytes and macrophages that enhanced IL-1β production. Zinc influx into monocytes and macrophages required the expression of the gene encoding the transporter Zip8. The authors identified the signaling pathway that was activated by zinc and that promoted the shift to glycolytic metabolism that was required for increased IL-1β production. In monocytes from rheumatoid arthritis patients, plasma zinc concentrations and Zip8 expression were increased, and Zip8 expression correlated with more severe disease. Thus, inhibiting zinc influx into monocytes and macrophages could prevent excessive inflammatory responses that occur in diseases such as rheumatoid arthritis. Abstract 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-1β 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-1β 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. Get full access to this article View all available purchase options and get full access to this article.