Abstract
Chronic immune-activation/inflammation driven by factors like microbial translocation is a key determinant of HIV/SIV disease progression. Although, extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for microRNAs (miRNAs) in regulating several aspects of the immune/inflammatory response, immune-cell proliferation, differentiation and activation. To understand their immunoregulatory role, we profiled miRNA expression sequentially in intestinal lamina propria leukocytes (LPLs) of eight macaques before and at 21, 90 and 180 days post infection (DPI). At 21DPI, ∼20 and 9 miRNAs were up and downregulated, respectively. However, at 90DPI (n=51) and 180DPI (n=44), ≥75% of miRNAs showed decreased expression. Notably, the T-cell activation associated miR-15b, miR-142-3p, miR-142-5p and miR-150 expression was significantly downregulated at 90 and 180DPI. Out of ∼10 downregulated miRNAs predicted to regulate CD69, we confirmed miR-92a to directly target CD69. Interestingly, the SIV-induced miR-190b expression was elevated at all timepoints. Additionally, elevated lipopolysaccharide (LPS)-responsive miR-146b-5p expression at 180DPI was confirmed in primary intestinal macrophages following LPS treatment in vitro. Further, reporter and overexpression assays validated IRAK1 as a direct miR-150 target. Furthermore, IRAK1 protein levels were markedly elevated in intestinal LPLs and epithelium. Finally, blockade of CD8+ T-cell activation/proliferation with delta-9 tetrahydrocannabinol (Δ9-THC) significantly prevented miR-150 downregulation and IRAK1 upregulation. Our findings suggest that miR-150 downregulation during T-cell activation may disrupt the translational control of IRAK1 facilitating persistent GI inflammation. Finally, the ability of Δ9-THC to block the miR-150-IRAK1 regulatory cascade highlights the potential of cannabinoids to inhibit persistent inflammation/immune-activation in HIV/SIV infection.
IMPORTANCE:
Persistent gastrointestinal tract (GI) disease/inflammation is a cardinal feature of HIV/SIV infection. Increasing evidence points to a critical role for microRNAs (miRNAs) in controlling several aspects of the immune/inflammatory response. Here, we show significant dysregulation of miRNA expression exclusively in the intestinal lamina propria cellular compartment through the course of SIV infection. Specifically, the study identified miRNA signatures associated with key pathogenic events such as viral replication, T-cell activation and microbial translocation. The T-cell enriched miR-150 showed significant downregulation throughout SIV infection and was confirmed to target IRAK1 (Interleukin-1 receptor 1 kinase), a critical signal-transducing component of the IL-1 receptor and TLR signaling pathways. Reduced miR-150 expression was associated with markedly elevated IRAK1 expression in the intestines of chronically SIV-infected macaques. Finally, delta-9 -tetrahydrocannabinol mediated blockade of CD8+ T cell activation in vitro significantly inhibited miR-150 downregulation and IRAK1 upregulation suggesting its potential for targeted immune modulation in HIV infection.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
- PMID:
- 26937033
- [PubMed – as supplied by publisher]
