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Cannabis Anti-Inflammatory/Reservoir Reduction(Cure)?
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"studies are warranted to determine whether supplementing cART with cannabinoids (non-psychotropic cannabidiol) can reduce residual intestinal inflammation and potentially the size of the gut-associated lymphoid tissue viral reservoir.....we demonstrate that long term, twice daily administration of Δ9-THC resulted in reduced expression of pro-inflammatory genes/micro-RNAs and inhibited T cell proliferation/activation without any adverse effects in cART-naive chronic SIV-infected rhesus macaques. "
"long-term Δ9-THC administration suppressed intestinal T cell proliferation/activation and programmed death-1 (PD-1) expression, increased intestinal CD163 anti-inflammatory macrophages, and reduced CD8+ T cell expansion in peripheral blood without any adverse effects.
Consistent with its immunomodulatory effects (11), long-term Δ9-THC administration effectively inhibited classical pro-inflammatory miRNA and gene expression in colons of chronically SIV-infected rhesus macaques.
Chronic intestinal inflammation is a common sequela to HIV/SIV replication and persists even in virally suppressed PLWH (8). This inflammation is detrimental as it can disrupt the intestinal epithelial barrier and promote microbial/byproduct translocation and interfere with absorption of cART drugs, both of which contribute to enhanced viral replication, systemic immune activation, HIV associated comorbidities and disease progression (8). Therefore, feasible pharmacological strategies to reduce/inhibit chronic intestinal inflammation are needed to increase cART efficacy and restore GI homeostasis and immune function. In the present study, we demonstrate that differential modulation of miRNA/gene expression and T cell proliferation/activation are potential mechanisms underlying the anti-inflammatory effects of Δ9-THC in chronic untreated SIV infection.
In summary, we demonstrate that long term, twice daily administration of Δ9-THC resulted in reduced expression of pro-inflammatory genes/micro-RNAs and inhibited T cell proliferation/activation without any adverse effects in cART-naive chronic SIV-infected rhesus macaques. More importantly, the anti-inflammatory effects extended to the lymph nodes, where extensive collagen deposition in B cell follicular regions was detected in VEH/SIV, but not in THC/SIV rhesus macaques. These novel findings together with recent legislation tolerating the medical use of marijuana suggest that future studies are warranted to determine whether supplementing cART with cannabinoids (non-psychotropic cannabidiol) can reduce residual intestinal inflammation and potentially the size of the gut-associated lymphoid tissue viral reservoir."
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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
https://www.frontiersin.org/articles/10.3389/fimmu.2019.00914/full
Vinay Kumar1, Workineh Torben2,Joshua Mansfield3, Xavier Alvarez3, Curtis Vande Stouwe4,Jian Li5,Siddappa N. Byrareddy6, Peter J. Didier3, Bapi Pahar3, Patricia E. Molina4,7 and Mahesh Mohan3*
• 1Nektar Therapeutics, South San Francisco, CA, United States
• 2Department of Biological Sciences, LSU, Alexandria, LA, United States
• 3Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
• 4Department of Physiology, LSUHSC, New Orleans, LA, United States
• 5Department of Global Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
• 6Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
• 7LSUHSC Alcohol and Drug Abuse Center, New Orleans, LA, 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). 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 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 14 and 150 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.
Inflammation and immune dysregulation directly or indirectly lead to most of the morbidity and mortality in HIV infection, even in virally suppressed PLWH (8). One of the proposed mechanisms driving chronic inflammation and systemic immune activation in HIV/SIV infection is intestinal microbial translocation, a pathogenic event triggered by persistent intestinal inflammation (8). In this context, chronic administration of Δ9-THC to SIV-infected rhesus macaques alleviated infection-induced inflammation and prolonged survival (10).
Consistent with its immunomodulatory effects (11), long-term Δ9-THC administration effectively inhibited classical pro-inflammatory miRNA and gene expression in colons of chronically SIV-infected rhesus macaques. In vitro studies showed that miR-204, a miRNA upregulated in the colon of THC/SIV rhesus macaques could potentially target and downregulate the expression of MMP8, an extracellular matrix-degrading collagenase produced by both neutrophils and colonic epithelium (CE) (12). Interestingly, the anti-inflammatory effects of cannabinoids extended beyond the intestine as Δ9-THC prevented peripheral lymph node fibrosis. Finally, and most importantly, long-term Δ9-THC administration suppressed intestinal T cell proliferation/activation and programmed death-1 (PD-1) expression, increased intestinal CD163 anti-inflammatory macrophages, and reduced CD8+ T cell expansion in peripheral blood without any adverse effects.
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