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.

Highly Bioactive MXene-M2-Exosome Nanocomposites Promote Angiogenic Diabetic Wound Repair through Reconstructing High Glucose-Derived Immune Inhibition

“…The M2-Exo release profile, antibacterial evaluation, and biocompatibility assessment of FM-Exo hydrogel were evaluated as detailed in SI Section S1. 4.…”

“…These factors collectively contribute to the challenges in achieving an efficient wound closure. The continuous inflammation delays the progression from inflammation to proliferation, representing a crucial mark that influences the proper healing of diabetic wounds. − Furthermore, the capacity of cells to proliferate and migrate is suppressed due to the numerous released inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6. Macrophages (Mφ) are one of the key immune cells regulating the process of inflammation, which can be activated and polarized into different phenotypes that are mainly classified as the classical-activated M1 phenotype showcasing pro-inflammation and alternative-activated M2 phenotype possessing anti-inflammation capacity .…”

Mechanisms of Nrf2 and NF-κB pathways in diabetic wound and potential treatment strategies

“…A potential therapy was found and con rmed that interferon (IFN) regulates Setdb2 expression in wound macrophages via type 1 interferon/janus kinase/signal transducer and activator of transcription 1 (IFN-1/JAK/STAT1) signaling, which promotes the transformation of macrophages from in ammation to repair and is bene cial for wound healing [99]. Interestingly, another study found that the increased expression of in ammatory genes was associated with the Jumonji domain-containing protein D3 (JMJD3) production in macrophages from diabetic wounds [100]. During the late stage of wound injury, IL-6 increases, regulating JMJD3 expression in macrophages through JAK1, while the increase expression of 3/STAT3 pathway and JMJD3 in late process can induce the NF-κB mediated transcription of in ammatory genes in macrophages by in uencing H3K27me3 [100].…”

“…Interestingly, another study found that the increased expression of in ammatory genes was associated with the Jumonji domain-containing protein D3 (JMJD3) production in macrophages from diabetic wounds [100]. During the late stage of wound injury, IL-6 increases, regulating JMJD3 expression in macrophages through JAK1, while the increase expression of 3/STAT3 pathway and JMJD3 in late process can induce the NF-κB mediated transcription of in ammatory genes in macrophages by in uencing H3K27me3 [100]. Further, the study showed that macrophage-speci c nanoparticles were effective at inhibiting JMJD3 in diabetic wounds, as well as reducing in ammation and accelerating wound healing [100].…”

“…During the late stage of wound injury, IL-6 increases, regulating JMJD3 expression in macrophages through JAK1, while the increase expression of 3/STAT3 pathway and JMJD3 in late process can induce the NF-κB mediated transcription of in ammatory genes in macrophages by in uencing H3K27me3 [100]. Further, the study showed that macrophage-speci c nanoparticles were effective at inhibiting JMJD3 in diabetic wounds, as well as reducing in ammation and accelerating wound healing [100]. In conclusion, macrophages and NF-κBmediated in ammation offer important therapeutic targets for diabetic wounds.…”