Abstract
Chronic inflammation underlies the development of metabolic diseases and individuals with metabolic disease often also suffer from delayed wound healing due to prolonged inflammation. Resolving inflammation provides a therapeutic strategy in treating metabolic diseases. We previously showed that during an anti-inflammatory response when macrophages were alternatively (M2) polarized, retinoic acid (RA) dramatically activated arginase 1 gene (Arg1), a gene crucial for wound healing. Here we report that a widely used sulfonylurea drug for type 2 diabetes mellitus (T2DM), glyburide, enhances the anti-inflammatory response and synergizes with RA to promote wound healing. Our data also delineate the mechanism underlying glyburide’s anti-inflammatory effect, which is to stimulate the degradation of a pro-inflammatory regulator, Receptor Interacting Protein 140 (RIP140), by activating Ca2+/calmodulin-dependent protein kinase II (CamKII) that triggers specific ubiquitination of RIP140 for degradation. By stimulating RIP140 degradation, glyburide enhances M2 polarization and anti-inflammation. Using a high-fat diet induced obesity mouse model to monitor wound healing effects, we provide a proof-of-concept for a therapeutic strategy that combining glyburide and RA can significantly improve wound healing. Mechanistically, this study uncovers a new mechanism of action of glyburide and a new pathway modulating RIP140 protein degradation that is mediated by CamKII signaling.
Highlights
Metabolic diseases such as Type II diabetes mellitus (T2DM) cast a huge burden on global health
The study is to test this therapeutic strategy for wound healing in a high fat diet (HFD)-induced obesity mouse model that mimics the condition of chronic inflammation
We uncover a new mechanism of action of glyburide, which is by stimulating protein degradation of a key inflammatory coregulator named nuclear receptor coregulator Receptor Interacting Protein 140 (RIP140) (Nrip1)
Summary
Metabolic diseases such as Type II diabetes mellitus (T2DM) cast a huge burden on global health These patients exhibit multiple symptoms such as hyperglycemia, insulin resistance, hypertension and dyslipidemia[1], as well as debilitating, delayed wound healing[2,3]. We have found that in macrophage polarization, a process essential to innate immunity, RA treatment significantly elevates the expression of Arginase 1 (Arg1), a gene product critical to wound healing process. Given that RA can boost Arg[1] expression, and that glyburide is potentially anti-inflammatory, we propose that combining RA and glyburide may be synergistically beneficial to the management of wounds, especially for patients suffering from, or in the process of developing, metabolic diseases. We have previously determined that RIP140 can be degraded by Syk-mediated tyrosine phosphorylation on Tyr[364], Tyr[418] and Tyr[436] in the pathological context of LPS-induced inflammation, which prevents septic shock[21]
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