Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair.

Abstract

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

• Authors: Christopher O Audu, William J Melvin, Amrita D Joshi, Sonya J Wolf, Jadie Y Moon, Frank M Davis, Emily C Barrett, Kevin D Mangum, Hongping Deng, Xianying Xing, Rachel Wasikowski, Lam C Tsoi, Sriganesh B Sharma, Tyler M Bauer, James Shadiow, Matthew A Corriere, Andrea T Obi, Steven L Kunkel, Benjamin Levi, Bethany B Moore, Johann E Gudjonsson, Andrew M Smith, Katherine A Gallagher
• Journal: Cellular & molecular immunology (Cell Mol Immunol) Vol. 19 Issue 11 Pg. 1251-1262 (11 2022) ISSN: 2042-0226 [Electronic] China
• PMID: 36127466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Cytokines

Topics

• Mice
• Humans
• Animals
• Diabetes Mellitus, Experimental
• Mice, Inbred C57BL
• Macrophages (metabolism)
• Wound Healing
• Inflammation (metabolism)
• Cytokines (metabolism)