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JMJD3 regulates diabetic wound repair in a STINGy fashion

Cellular & Molecular Immunology volume 20, pages 110–111 (2023)Cite this article

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Skin wound repair is a multifactorial process involving immune and nonimmune cells, such as mast cells, neutrophils, lymphocytes, monocytes, macrophages, keratinocytes, fibroblasts, and endothelial cells. In diabetic patients, this process is significantly hindered, resulting in chronic complications, such as diabetic foot, which is typically associated with difficult-to-heal ulcers1. Recently, the roles of monocytes, their derived macrophages, and skin-resident macrophages in cutaneous wound repair have gained significant appreciation. The conversion of macrophages from M1-like inflammatory cells to M2-like reparative cells has been associated with metabolic dysregulation under diabetic conditions. Reparative cytokines, angiogenic factors, and growth factors released by M2 macrophages are believed to be key contributors to proper wound repair. The persistence of M1 macrophages and the inflammatory state during diabetes or in response to a high-fat diet results in nonhealing wounds.

Audu et al.2 showed that myeloid expression of the DNA demethylase JMJD3 resulted in the persistence of NF-κB-mediated inflammatory gene expression during diabetic wound healing. JMJD3 expression seems to be regulated by the JAK1/3-STAT1-IL-6 axis in both human and mouse diabetic wounds. Importantly, the authors show that the increase in JMJD3 levels is restricted to the early inflammatory phase of wound repair under nondiabetic conditions, while under diet-induced obesity, there is a delay in JMJD3 expression. This pattern is paralleled by the expression of STING, TNF-α, IL-6, and IL-1β but not IFN-β. Myeloid-specific deletion of JMJD3 results in a significant reduction in STING expression. STING-deficient diabetic mice showed enhanced wound closure associated with increased collagen deposition and macrophage conversion from the M1 to the M2 phenotype. Furthermore, STING activation in macrophages in diabetic wounds seems to be controlled by IL-6. Finally, nanoparticles loaded with the JMJD3 inhibitor GSK-J1 showed enhanced wound repair (as did JMJD3f/fLyzCre+ mice) in diabetic mice, and these effects were associated with reduced STING and inflammatory cytokine expression by wound macrophages.

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Acknowledgements

This work was supported by the Israeli Science Foundation (grant no. 1207/22 to AA). Fig. 1 was generated with BioRender.com.

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  1. Departments of Biology and Human Biology, University of Haifa, Haifa, Israel

    Amiram Ariel

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Correspondence to Amiram Ariel.

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Ariel, A. JMJD3 regulates diabetic wound repair in a STINGy fashion. Cell Mol Immunol 20, 110–111 (2023). https://doi.org/10.1038/s41423-022-00937-3

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