CCL8/MCP‐2 is a target for mir‐146a in HIV‐1‐infected human microglial cells

Abstract

MicroRNA-mediated regulation of gene expression appears to be involved in a variety of cellular processes, including development, differentiation, proliferation, and apoptosis. Mir-146a is thought to be involved in the regulation of the innate immune response, and its expression is increased in tissues associated with chronic inflammation. Among the predicted gene targets for mir-146a, the chemokine CCL8/MCP-2 is a ligand for the CCR5 chemokine receptor and a potent inhibitor of CD4/CCR5-mediated HIV-1 entry and replication. In the present study, we have analyzed changes in the expression of mir-146a in primary human fetal microglial cells upon infection with HIV-1 and found increased expression of mir-146a. We further show that CCL8/MCP-2 is a target for mir-146a in HIV-1 infected microglia, as overexpression of mir-146a prevented HIV-induced secretion of MCP-2 chemokine. The clinical relevance of our findings was evaluated in HIV-encephalitis (HIVE) brain samples in which decreased levels of MCP-2 and increased levels of mir-146a were observed, suggesting a role for mir-146a in the maintenance of HIV-mediated chronic inflammation of the brain.

miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions

“…[30][31][32][33] Abnormal expression of miRNAs appears to be a common feature of many human diseases, ranging from cardiovascular disorders to cancer [30][31][32][33] and most recently inflammatory diseases. 9,34,35 Here, we present evidence showing that overexpression of the GSK3β inhibitor-dependent miRNAs, miR-98 and let-7g*, can decrease leukocyte adhesion to and migration across the BBB, in both in vitro and in vivo models. Not all miRNAs had similar abilities to improve BBB function in an in vitro model.…”

“…8 For instance, miR-155 and miR-146a regulate a variety of immune reactions, including production of cytokines by T and B cells and the germinal center B-cell response. 9 miRNA profiling suggests that miR-126 is expressed mainly in endothelial cells. 10 Additional endothelial miRNA clusters have been identified: miR-17-92, miR-23-27-24, and miR-222-221 (many miRNAs are encoded by polycistronic miRNA genes).…”

Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells

“…Upon lipopolysaccharide (LPS) stimulation and virus infection, miR-146a acts as a negative feedback regulator and restrains the Toll-like receptor signaling pathways by targeting IRAK1/2 and TRAF6 in various innate cells such as monocytes, lung epithelial alveolar cells, and microglial cells. [7][8][9][10] In the adoptive immune system, miR-146a has previously been reported to target Fas-Associated protein with Death Domain to modulate activation-induced cell death and interleukin-2 (IL-2) expression in Jurkat T cells. 11 Ablation of miR-146a in mice leads to increased numbers of Treg cells but impairs their suppressor function because of the unrestrained function of STAT1.…”

Epigenetics and the Modulation of Neuroinflammation

“…Increased IRF-3 can, in turn, further exacerbate neuroinflammation by promoting the expression of miR-155 [48], suggesting a mechanism by which Tat exposure may further amplify chronic inflammation that contributes to eventual neurological dysfunction in HAND. It has also been reported that infection of microglia by HIV leads to increased expression of miR-146a, which subsequently suppress proinflammatory behavior and the release of CCL8/monocyte chemoattractant protein 2 (MCP-2) [49]. As MCP-2 can serve to block cellular entry by HIV, the role of miR-146a may have duel effect in perpetuating HAND by both suppressing endogenous antiviral proteins and decreasing the release of MCP-2.…”