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

Kim, Bonah; Kim, Hee Young; Yoon, Bo Ruem; Yeo, Jina; Jung, Ji In; Yu, Kyung‐Sang; Kim, Hyeon Chang; Yoo, Seung‐Min; Park, Jin Kyun; Kang, Seong Wook; Lee, Won Woo

doi:10.1126/scisignal.abi7400

Cited by 21 publications

(17 citation statements)

References 72 publications

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“…Bioavailable zinc in the monocyte cytoplasm is essential for protein phosphatase 2 phosphatase activator inhibition and mTORC1/p-S6K phosphorylation. Zip8 expression is associated with IL-1b production in monocytes/ macrophages in severe arthritis (104). Immunostaining confirmed that glycogen synthase kinase 3b expression is prevalent in macrophages in the RA-injured synovium, and glycogen synthase kinase 3b inactivation is a metabolic switch that induces mitochondria in macrophages to use oxygen inefficiently to produce sufficient ATP (105).…”

Section: Ramentioning

confidence: 78%

“…Both undifferentiated monocytes and macrophages in RA are in a hypermetabolic state (148). IL-1b, which is a consequence of metabolic reprogramming, seems to be a vital contributor to the pathogenesis of RA (102)(103)(104)(105)(106)(107)(108). Cinnamaldehyde inhibits the expression of the succinate receptor 1 and the accumulation of succinate, leading to restricted HIF-1a activation and ultimately limiting glycolytic activity (102).…”

Section: Ramentioning

confidence: 99%

“…Impairing macrophage glycolysis in RA is associated with inflammasome disassembly, decreased IL-1b production, and arthritis remission (102). The cellular membrane zinc transporter Zip8 is reported to be present at higher levels in the synovial tissue of patients with RA than in healthy volunteers (104). Bioavailable zinc in the monocyte cytoplasm is essential for protein phosphatase 2 phosphatase activator inhibition and mTORC1/p-S6K phosphorylation.…”

Section: Ramentioning

confidence: 99%

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Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Chen

Zhang

et al. 2022

Front. Immunol.

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Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine–threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

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Section: Ramentioning

confidence: 78%

Section: Ramentioning

confidence: 99%

Section: Ramentioning

confidence: 99%

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Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Chen

Zhang

et al. 2022

Front. Immunol.

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“…As a common pro-inflammatory cytokine, IL-1β is secreted by most innate immunity cells, including neutrophils, monocytes, and macrophages. Once innate immunity cells recognize the pathogens, they would secrete IL-1β to promote inflammatory responses, including the generation of ROS to kill pathogens (34). As a result, the concentration of IL-1β could indicate the body infection.…”

Section: Discussionmentioning

confidence: 99%

Supplementation With Zinc Proteinate Increases the Growth Performance by Reducing the Incidence of Diarrhea and Improving the Immune Function of Dairy Calves During the First Month of Life

Jin

Gao

et al. 2022

Front. Vet. Sci.

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Two experiments were conducted to identify the optimal dose of zinc proteinate (ZP) in the diet for dairy calves and then to compare early supplementation with the ZP or zinc methionine (ZM) on the growth performance, incidence of diarrhea, antioxidant status, and immune function of dairy calves during their first month of life. In Experiment 1, forty newborn female Holstein dairy calves were randomly divided into four groups (n = 10): a control group (without ZP supplementation, ZP0) or groups that received ZP supplementation at 40, 80, and 120 mg zinc/day, respectively (ZP40, ZP80, and ZP120). The experiment lasted 14 days, and the growth performance, incidence of diarrhea, and serum zinc concentration were analyzed. In Experiment 2, thirty-six newborn female Holstein dairy calves were randomly allocated to three groups (n = 12): a negative control group (without zinc supplementation, CON), a positive control group (supplemented with 80 mg zinc/day in the form of zinc methionine, ZM), and a ZP group (supplemented with 80 mg zinc/day in the form of ZP). The experiment lasted 28 days, and the growth performance, incidence of diarrhea, serum zinc concentration, serum antioxidant indicators, and concentrations of plasma immunoglobulins and cytokines were determined on days 7, 14, 21, and 28. Results showed that in Experiment 1, supplementation with ZP to yield 80 mg zinc/day increased the ADG (P < 0.01) and serum zinc concentration (P < 0.01), and decreased the F/G (P < 0.01) and the incidence of diarrhea (P < 0.05) during days 1–14. In Experiment 2, compared with the CON group, ZP increased the ADG (P < 0.01), serum zinc concentration (P < 0.01), and plasma immunoglobulin G (IgG; P < 0.01) and IgM (P < 0.01) concentrations, but reduced the incidence of diarrhea (P < 0.01), serum malondialdehyde (P < 0.01), and plasma interleukin-1β (P < 0.01) concentrations during days 1–28. Overall, ZP supplementation to yield 80 mg zinc/day improves the growth performance and immune function, and decrease the incidence of diarrhea of dairy calves, which was comparable to the same dose of zinc in the form of ZM.

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“…Zn is second only to iron as the most abundant trace mineral in humans in our body. Research has focused on the utility of this transition metal in the immunologic system (7)(8)(9)(10). It seems that this trace element may boost immune function, soothe glycemia levels, and help keep cardiac, ocular, and cutaneous systems healthy, targeting the T-cell metabolism intimately (11)(12)(13).…”

mentioning

confidence: 99%

The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion

Sergi

2022

Front. Immunol.

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

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

Cited by 21 publications

References 72 publications

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Supplementation With Zinc Proteinate Increases the Growth Performance by Reducing the Incidence of Diarrhea and Improving the Immune Function of Dairy Calves During the First Month of Life

The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion

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