Luciano Ribeiro Filgueiras1, Stephanie L Brandt2, Theresa Raquel de Oliveira Ramalho3, Sonia Jancar3, C Henrique Serezani2. 1. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508, Brazil. Electronic address: luciano.ribeiro@usp.br. 2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 3. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508, Brazil.
Abstract
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 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/ INTERPRETATION: 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.
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 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabeticmice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabeticmice 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 diabeticmice 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/ INTERPRETATION: These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabeticmice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.
Authors: Jenny E Kanter; Farah Kramer; Shelley Barnhart; Michelle M Averill; Anuradha Vivekanandan-Giri; Thad Vickery; Lei O Li; Lev Becker; Wei Yuan; Alan Chait; Kathleen R Braun; Susan Potter-Perigo; Srinath Sanda; Thomas N Wight; Subramaniam Pennathur; Charles N Serhan; Jay W Heinecke; Rosalind A Coleman; Karin E Bornfeldt Journal: Proc Natl Acad Sci U S A Date: 2012-01-17 Impact factor: 11.205
Authors: Daniele P Santos-Bezerra; Luciano R Filgueiras; Maria Beatriz Monteiro; Sharon N Admoni; Ricardo V Perez; Ana M Cavaleiro; Cleide G Machado; Ubiratan F Machado; Marisa Passarelli; Sonia Jancar; Maria Lucia Correa-Giannella Journal: Mediators Inflamm Date: 2020-03-23 Impact factor: 4.711