10.3389/fimmu.2019.00914.s012 Vinay Kumar Vinay Kumar Workineh Torben Workineh Torben Joshua Mansfield Joshua Mansfield Xavier Alvarez Xavier Alvarez Curtis Vande Stouwe Curtis Vande Stouwe Jian Li Jian Li Siddappa N. Byrareddy Siddappa N. Byrareddy Peter J. Didier Peter J. Didier Bapi Pahar Bapi Pahar Patricia E. Molina Patricia E. Molina Mahesh Mohan Mahesh Mohan Image_2_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.TIF Frontiers 2019 THC SIV rhesus macaque intestinal inflammation micro-RNA 2019-04-30 04:34:40 Figure https://frontiersin.figshare.com/articles/figure/Image_2_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_TIF/8056598 <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; n = 9) or Δ<sup>9</sup>-tetrahydrocannabinol (Δ<sup>9</sup>-THC; THC/SIV; n = 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 MUC13, keratin-8 (stress protection), PROM1 (epithelial proliferation), and anti-HIV CCL5. 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>