Patients with type 2 diabetes mellitus (T2DM) have impaired wound healing owing to the dominance of the proinflammatory M1 macrophage phenotype. New research reveals that, under diabetic conditions, lysine-specific demethylase 6B (also known as JMJD3) demethylates the lysine 27, histone 3 (H3K27Me3) mark that supresses IL-12 expression, which results in increased IL-12 production and polarization of macrophages to an M1 phenotype.
“Macrophages isolated from patients with T2DM produce excess proinflammatory mediators; however, the molecular mechanisms that programme and sustain these phenotypes were unclear,” explains lead author Katherine Gallagher.
Gallagher's team showed that bone-marrow-derived (BMD) stem or progenitor cells and macrophages from glucose intolerant, obese mice had significantly reduced H3K27 methylation in the IL-12 promoter region. In the same cells, and in BMD cells from patients with T2DM, significantly increased JMJD3 and IL12 gene expression were also apparent. Inhibition of JMJD3 resulted in a significant reduction in IL12 expression in mouse BMD cells. “The H3K27Me3 epigenetic mark is passed on to more-differentiated recruited macrophages found in the wound tissue. Thus, peripheral tissue is 'preprogrammed' towards chronic inflammation,” Gallagher explains. This finding suggests the H3K27Me3 mark might set a 'metabolic memory' in chronic wound inflammation and other inflammatory diabetic complications. “These mechanisms may provide a novel explanation for the altered clinical phenotypes associated with the pathology of diabetic wounds,” Gallagher concludes.
References
Gallagher, K. A. et al. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 10.2337/db14-0872
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Sidaway, P. Epigenetic changes lead to impaired wound healing in patients with T2DM. Nat Rev Endocrinol 11, 65 (2015). https://doi.org/10.1038/nrendo.2014.207
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DOI: https://doi.org/10.1038/nrendo.2014.207
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