Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice.
OBJECTIVE
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 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 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 qPCR.


RESULTS
Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression.


CONCLUSIONS
These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508, Brazil. Electronic address: luciano.ribeiro@usp.br.
Luciano Ribeiro
LR
Filgueiras
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Stephanie L
SL
Brandt
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508, Brazil.
Theresa Raquel de Oliveira
TR
Ramalho
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508, Brazil.
Sonia
S
Jancar
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
C Henrique
CH
Serezani
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009994:Osmolar Concentration; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000633:toxicity
D004791:Enzyme Inhibitors; D006657:Histones; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D013311:Streptozocin; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D005947:Glucose
Diabetes; Epigenetic; Histone acetylation; Inflammation; Macrophage; Metabolic memory