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

Abstract

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 9 -tetrahydrocannabinol (Δ 9 -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 9 -THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that Δ 9 -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 Δ 9 -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 Δ 9 -THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

Long-Term Low-Dose Delta-9-Tetrahydrocannbinol (THC) Administration to Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques Stimulates the Release of Bioactive Blood Extracellular Vesicles (EVs) that Induce Divergent Structural Adaptations and Signaling Cues

“…Numerous studies, including studies from our group [ 8 , 9 , 10 , 11 , 12 ], showed that administration of THC is linked to a beneficial reduction in systemic inflammation and immune activation in ART-treated HIV+ individuals. In the SIV/rhesus macaque model, THC was shown to ameliorate SIV disease progression [ 24 , 25 ], reduce intestinal T cell activation/exhaustion and prevent lymph node fibrosis [ 10 ]. The benefits of THC are systemic, affect many organs, and are also present in BEVs, which may mediate THC action, as shown by the results of the present study.…”

“…The optimization of the THC dosing in rhesus macaques accounts for the development of tolerance during the initial period of administration. Because this dose of THC showed protection in our previously published studies [ 10 ], the same dose was used in this study. SIV levels in plasma were quantified by using the TaqMan One-Step Real-Time RT-qPCR assay that targeted the long terminal repeats (LTRs) gene [ 10 ].…”

“…Because this dose of THC showed protection in our previously published studies [ 10 ], the same dose was used in this study. SIV levels in plasma were quantified by using the TaqMan One-Step Real-Time RT-qPCR assay that targeted the long terminal repeats (LTRs) gene [ 10 ]. Blood samples were collected monthly in 4.9 mL EDTA containing vacutainer tubes following the standard operating protocols established for blood collection from non-human primates at the TNPRC.…”

“…Cannabinoids, the chemical compounds found in the cannabis (marijuana) plant, exhibit pharmacobiological effects in various conditions, including remyelination [ 1 ], hyperthermia [ 2 ], hypothermia [ 3 ], catalepsy [ 4 , 5 ], inflammation and immune activation [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ], analgesia [ 13 ], cellular growth/arrest, apoptosis [ 14 ], as well as alteration in the functions of a variety of immune cells [ 15 , 16 , 17 , 18 ]. Although more than 100 cannabinoids have been identified in cannabis, THC and the non-psychotropic cannabidiol (CBD) are the most widely used and both have the same molecular formula (C 21 H 30 O 2 ) and molecular weight (314.5 g/mol).…”

Kannabinoid Tip 2 Reseptör Agonistinin Sıçanlarda Over İskemi/reperfüzyon Hasarına Karşı Koruyucu Etkisi

“…7 Infl ammation-induced improvements in vascular permeability result in the accumulation of more fl uid in endothelial cells than can be absorbed. 8 In previously studies on cannabinoid (CB) agonists, they have been found to reduce the antinociceptive and anti-infl ammatory eff ects of CB agonists. 3,9,10 In particular, they have been found to mediate the eff ects of antiedema and anti-infl ammatory through peripheral CB2 receptors.…”