AUTHOR=Kumar Vinay , Torben Workineh , Mansfield Joshua , Alvarez Xavier , Vande Stouwe Curtis , Li Jian , Byrareddy Siddappa N. , Didier Peter J. , Pahar Bapi , Molina Patricia E. , Mohan Mahesh 

TITLE=Cannabinoid Attenuation of Intestinal Inflammation in Chronic SIV-Infected Rhesus Macaques Involves T Cell Modulation and Differential Expression of Micro-RNAs and Pro-inflammatory Genes

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00914

DOI=10.3389/fimmu.2019.00914

ISSN=1664-3224

ABSTRACT=<p>Cannabis use is frequent in HIV-infected individuals for its appetite stimulation and anti-inflammatory effects. To identify the underlying molecular mechanisms associated with these effects, we simultaneously profiled micro-RNA (miRNA) and mRNA expression in the colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques administered either vehicle (VEH/SIV; <italic>n</italic> = 9) or Δ<sup>9</sup>-tetrahydrocannabinol (Δ<sup>9</sup>-THC; THC/SIV; <italic>n</italic> = 8). Pro-inflammatory miR-130a, miR-222, and miR-29b, lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV rhesus macaques. Compared to VEH/SIV rhesus macaques, 10 miRNAs were significantly upregulated in THC/SIV rhesus macaques, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV rhesus macaques. Moreover, THC/SIV rhesus macaques failed to upregulate pro-inflammatory miR-21, miR-141 and miR-222, and alpha/beta-defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV rhesus macaques showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory <italic>MUC13</italic>, keratin-8 (stress protection), <italic>PROM1</italic> (epithelial proliferation), and anti-HIV <italic>CCL5</italic>. Gomori one-step trichrome staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but not in THC/SIV rhesus macaques, thus demonstrating the ability of Δ<sup>9</sup>-THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that Δ<sup>9</sup>-THC suppressed intestinal T cell proliferation/activation (Ki67/HLA-DR) and PD-1 expression and increased the percentages of anti-inflammatory CD163<sup>+</sup> macrophages. Finally, while Δ<sup>9</sup>-THC did not affect the levels of CD4<sup>+</sup> T cells, it significantly reduced absolute CD8<sup>+</sup> T cell numbers in peripheral blood at 14 and 150 days post-SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in Δ<sup>9</sup>-THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.</p>