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Front. Immunol. | doi: 10.3389/fimmu.2019.00914

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

Vinay Kumar1, Workineh Torben2, Joshua Mansfield3, Xavier Alvarez3, Curtis Vande Stouwe4,  Jian Li5,  Siddappa Byrareddy6,  Peter J. Didier3,  Bapi Pahar3, Patricia E. Molina4 and  Mahesh Mohan3*
  • 1Nektar Therapeutics, United States
  • 2Louisiana State University, United States
  • 3Tulane National Primate Research Center, School of Medicine, Tulane University, United States
  • 4LSU Health Sciences Center New Orleans, Louisiana State University, United States
  • 5Tulane University Health Sciences Center, United States
  • 6University of Nebraska Medical Center, United States

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 Δ9- tetrahydrocannabinol (Δ9-THC; THC/SIV; n=8). Proinflammatory 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 proinflammatory 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 none of the THC/SIV rhesus macaques, thus demonstrating the ability of Δ9-THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that Δ9-THC suppressed intestinal T cell proliferation/activation (Ki67/HLA-DR) and PD-1 expression and increased the percentages of anti-inflammatory CD163+ macrophages. Finally, while Δ9-THC did not affect the levels of CD4+ T cells, it significantly reduced absolute CD8+ T cell numbers in peripheral blood at 150 and 180 days post-SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in Δ9-THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

Keywords: Delta9-tetrahydro cannabinol, SIV (Simian Immunodeficiency Virus, Rhesus macaque model, intestinal inflammation, Lymph node fibrosis, Matrixmetalloprotease 8, miR-204

Received: 03 Aug 2018; Accepted: 09 Apr 2019.

Edited by:

Stefano Caserta, University of Hull, United Kingdom

Reviewed by:

John Zaunders, St Vincent’s Hospital Sydney, Australia
Slava Rom, Lewis Katz School of Medicine, Temple University, United States  

Copyright: © 2019 Kumar, Torben, Mansfield, Alvarez, Vande Stouwe, Li, Byrareddy, Didier, Pahar, Molina and Mohan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mahesh Mohan, Tulane National Primate Research Center, School of Medicine, Tulane University, Covington, United States, mmohan@tulane.edu