| First Author | Wolf SJ | Year | 2024 |
| Journal | Diabetes | Volume | 73 |
| Issue | 9 | Pages | 1462-1472 |
| PubMed ID | 38869447 | Mgi Jnum | J:361326 |
| Mgi Id | MGI:7714465 | Doi | 10.2337/db23-0968 |
| Citation | Wolf SJ, et al. (2024) Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling. Diabetes 73(9):1462-1472 |
| abstractText | Macrophage (Mphi) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mphis persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mphis; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mphis through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns. We found that IL-1alpha is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mphi Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mphis late post-injury and is induced by IL-1alpha from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3f/flyz2Cre+), we demonstrate that JMJD3 controls Mphi-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1alpha/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mphis. These data also highlight the importance of cell cross-talk in wound tissues and identify JMJD3 and the IL-1R signaling cascade as important upstream therapeutic targets for Mphi NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds. |
