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MicroRNA-130a and miR-212 disrupt the intestinal epithelial barrier through modulation of peroxisome proliferator-activated receptor gamma and occludin expression in chronic SIV-infected rhesus macaques

ABSTRACT: We profiled and characterized mRNA expression exclusively in colonic epithelium (CE) of 4 chronically SIV-infected and 4 control rhesus macaques (RMs). Further analysis identified significant dowregulation of genes Genes associated with ion transport, epithelial barrier integrity/function, protection against oxidative injury, double stranded DNA damage repair and autophagy. Similarly, mRNA expression of genes associated with interferon response, anti-microbial defense, apoptosis, oxidative DNA damage, endoplasmic reticulum stress and inflammasome signaling were markedly upregulated.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE104771 | GEO | 2018/02/01

REPOSITORIES: GEO

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Project description:Intestinal epithelial barrier dysfunction is a well-known sequela of HIV/SIV infection that persists despite antiretroviral therapy. Although inflammation is a triggering factor, the underlying molecular mechanisms remain unknown. Emerging evidence suggests that epithelial barrier function is epigenetically regulated by inflammation-induced microRNAs (miRNAs). Accordingly, we profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium and identified 46 differentially expressed miRNAs (20 upregulated and 26 downregulated) in chronically SIV-infected rhesus macaques (Macaca mulatta). We bioinformatically crossed the predicted miRNA targets to transcriptomic data and characterized miR-130a and miR-212 as both were predicted to interact with critical epithelial barrier-associated genes. Next, we characterized peroxisome proliferator-activated receptor ? (PPAR?) and occludin (OCLN), predicted targets of miR-130a and miR-212, respectively, as their downregulation has been strongly linked to epithelial barrier disruption and dysbiosis. Immunofluorescence, luciferase reporter, and overexpression studies confirmed the ability of miR-130a and miR-212 to decrease protein expression of PPAR? and OCLN, respectively, and reduce transepithelial electrical resistance. Because ?-9-tetrahydrocannabinol exerted protective effects in the intestine in our previous studies, we successfully used it to reverse miR-130a- and miR-212-mediated reduction in transepithelial electrical resistance. Finally, ex vivo ?-9-tetrahydrocannabinol treatment of colon tissue from chronically SIV-infected rhesus macaques significantly increased PPAR? expression. Our findings suggest that dysregulated miR-130a and miR-212 expression in colonic epithelium during chronic HIV/SIV infection can facilitate epithelial barrier disruption by downregulating OCLN and PPAR? expression. Most importantly, our results highlight the beneficial effects of cannabinoids on epithelial barrier function in not just HIV/SIV but potentially other chronic intestinal inflammatory diseases.

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MicroRNA-130a and miR-212 disrupt the intestinal epithelial barrier through modulation of peroxisome proliferator-activated receptor gamma and occludin expression in chronic SIV-infected rhesus macaques

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