Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing. Issue 12 (20th July 2020)

• Record Type: Journal Article
• Authors: Davis, Frank M.; denDekker, Aaron; Joshi, Amrita D.; Wolf, Sonya J.; Audu, Christopher; Melvin, William J.; Mangum, Kevin; Riordan, Mary O.; Kunkel, Steven L.; Gallagher, Katherine A.
• Is Part Of: European journal of immunology. Volume 50:Issue 12(2020)
• Page Start: 1929
• Page End: 1940
• Publication Date: 2020-07-20
• Subjects: Diabetes -- Epigenetics -- Macrophage -- Toll‐like receptor -- Wound; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202048651
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte‐macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB‐mediated inflammatory gene promoters driving macrophage‐mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate‐induced Jmjd3 expression is controlled via TLR4/MyD88‐dependent signaling mechanism, where genetic depletion of TLR4 ( Tlr4 −/− ) or MyD88 ( MyD88 −/− ) negated the palmitate‐induced changes in Jmjd3 and downstream NFκB‐induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK‐J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3‐mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor‐based therapy may represent a novel treatment for nonhealing diabetic wounds. Abstract : Palmitate drives chronic macrophage mediated inflammation in diabetic tissue via upregulation of the histone demethylase, Jmjd3, and a histone demethylase inhibitor‐based therapy may represent a novel treatment for non∖healing diabetic wounds.