Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice

Aims: To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice. Methods: To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5 mM (low) or 25 mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone I-13 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by OCR. Results: Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6 days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Statl/Mycl88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression. Conclusions/interpretation: These results indicate that histone acetylation drives elevated Statl/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.