title: Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: Role of microRNA.
abstract: Glucocorticoid (GC) resistance is a severe problem associated with various inflammatory diseases. Previous studies have shown that repeated social stress induces GC resistance in innate immune cells, but the underlying molecular mechanisms have not been fully elucidated. Therefore, the purpose of this study was to examine potential underlying molecular mechanism(s) of repeated social defeat (RSD) stress on GC resistance in splenic macrophages. It was hypothesized that mRNA expression of receptors for GC and nuclear translocating-associated regulators in splenic macrophages would be affected by RSD, and that these changes would be associated with epigenetic modification. The data showed that the mRNA expression of GC and mineralocorticoid receptors were significantly decreased in splenic macrophages by RSD. RSD also induced a significantly decreased mRNA expression in FK506-binding protein 52 (FKBP52), consequently resulting in a significantly increased ratio of FKBP51 to FKBP52. Moreover, DNA methyltransferases 3a and 3b showed a significant decrease in their mRNA expression in the RSD group as did mRNA expression of histone deacetyltransferase 2. The RSD group also showed a significantly reduced quantity of methylated DNA in splenic macrophages. Based on microRNA (miRNA) profiling data, it was determined that RSD induced significantly increased expression of 9 different miRNAs that were predicted to interact with mRNAs of the GC receptor (6 miRNAs), mineralocorticoid receptor (3 miRNAs) and FKBP52 (2 miRNAs). Spearman correlation analysis revealed significantly strong correlations between the expression of 2 miRNAs and their target mRNA expression for GC receptors. Among these miRNAs, we verified direct effects of miRNA-29b and -340 overexpression on mRNA expression of GC receptors in L929 cells. The overexpression of miRNA-29b or -340 in L929 cells significantly reduced LPS-induced overexpression of GC receptors. In conclusion, this study provides evidence that epigenetic regulation, such as DNA methylation and miRNA expression, may play a role in the RSD-induced GC resistance that we have observed in splenic macrophages.
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Epithelial Biology Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Taewan
authors.initials: T
authors.lastname: Kim
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tarr
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.
authors.forename: Brenda
authors.initials: B
authors.lastname: Reader
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Powell
authors.affiliation: Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, United States. Electronic address: John.Sheridan@osumc.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Sheridan
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D012919:Social Behavior; D013154:Spleen / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C575863:NR3C1 protein, mouse; C000598932:Nr3c2 protein, mouse; C403485:tacrolimus binding protein 4
keywords: Chronic social stress; Epigenetics; Glucocorticoid insensitivity; Innate immunity; Macrophages; miRNA