Diabetic wound keratinocytes induce macrophage JMJD3-mediated Nlrp3 expression via IL1R signaling

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Abstract Type 2 diabetic (T2D) wound Macrophages (Mϕs) display a delayed chronic inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome gene expression and activation in Mϕs contributes to impaired wound healing in T2D and is induced by diabetic wound environment factors, yet the molecular mechanisms regulating this are unclear. Our lab has shown that keratinocytes regulate Mϕ phenotype during wound healing by producing proinflammatory cytokines. Thus, this project explores the molecular mechanisms by which keratinocytes drive increased Nlrp3 expression in diabetic wound Mϕs. Here, we found that Nlrp3 expression is increased in diabetic wound Mϕs late post-injury, and this can be induced by stimulation of Mϕs with diabetic wound keratinocyte supernatant. Further, we found that stimulation of Mϕs with diabetic wound keratinocyte supernatant decreased H3K27me3 deposition at the Nlrp3 promoter. Using genetically engineered mice (Jmjd3 fl/fl lyz2cre), we demonstrate that JMJD3, a demethylase specific for H3K27, controls Mϕ-mediated Nlrp3 expression and inflammasome activation during wound healing. Importantly, we show that diabetic wound keratinocytes induce Jmjd3 expression in Mϕs via IL1R/MyD88 upstream signaling. Interestingly, we found that IL1α is increased in human and murine wound diabetic keratinocytes compared to non-diabetic controls and stimulation of Mϕs with IL1α increases Nlrp3 expression via a JMJD3-mediated mechanism. Thus, our data suggest a role for keratinocyte IL1α in driving increased Nlrp3 expression in diabetic wound Mϕs via JMJD3. Continued investigation into the keratinocyte-Mϕ axis is key to developing novel treatments for non-healing T2D wounds. P30 DK089503, 1K99DK133828-01, 5K12 GM111725

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