Elevated histone acetylations in Müller cells contribute to inflammation: a novel inhibitory effect of minocycline.
Inflammation plays important roles in the development of diabetic retinopathy (DR). How Müller cells contribute to DR-related inflammation remains unclear. We hypothesized that under diabetic conditions, elevated histone acetylations in Müller cells contribute to the inflammatory response. In this study, significantly increased histone acetylations, elevated histone acetyltranferases levels, and decreased histone deacetylases levels were found in the retinas of diabetic rats. Elevated AcH3K9 and AcH3K18 were partially co-stained with Müller cells on retinal sections by immunofluorescence staining. Consistently, high-glucose (HG) treated rMC-1 cells, a Müller cell line, also showed upregulation of acetylated histones, accompanied with the overexpression of GFAP, p-STAT3, and NFκB-p65, and two inflammatory genes, TNFα and MCP-1. Meanwhile, sodium butyrate (NaB)-induced upregulation of acetylated histones is also accompanied with transcription of inflammatory genes. Minocycline, a drug with beneficial effects on DR, was found to downregulate HG-induced Müller cell activation, inflammation, and acetylated H3K18 bound to the promoters of GFAP and inflammatory genes by chromatin immunoprecipitation assay. Furthermore, the effects of minocycline on HG-induced elevation in histone acetylations were also demonstrated in isolated primary rat Müller cells. These findings suggest the elevation of histone acetylations in Müller cells plays important regulating roles in the inflammatory response during diabetic conditions. Inhibition of histone acetylation by minocycline is a novel function that may contribute to its beneficial effects on DR.
College of Life Sciences, Wuhan University, Wuhan 430072, People's Republic of China.
Lei-Lei
LL
Wang
Hong
H
Chen
Kun
K
Huang
Ling
L
Zheng
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006657:Histones / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D006657:Histones; D018836:Inflammation Mediators; D008911:Minocycline