Figure 12.

Potential anti-inflammatory mechanisms of delta-9-tetrahydrocannabinol (Δ⁹-THC) action in the intestine during HIV/SIV infection. During acute HIV/SIV infection, high viral replication in the intestine leads to massive CD4⁺ T-cell depletion resulting in pro-inflammatory cytokine production and subsequent T-cell hyperactivation. However, concurrent administration of cannabinoids (Δ⁹-THC) reduced CD4⁺ and CD8⁺ T-cell proliferation/activation (Ki67) and PD-1 expression. During intestinal inflammation, neutrophils migrate across the apical side of lining epithelium into the lumen, where they can cause damage to the epithelial cells (12). Δ⁹-THC can block neutrophil migration by acting via the CB2 receptor (9). Further, Δ⁹-THC prevented downregulation of ABCB1 (also called P-glycoprotein), an ATP-dependent drug efflux pump recently implicated in the luminal secretion of endocannabinoids that inhibited neutrophil activation and transmigration and subsequent epithelial damage (53) Furthermore, MMP-8 produced by epithelial cells and neutrophils degrades collagen to produce the tripeptide proline-glycine-proline, a strong neutrophil chemoattractant (12). Δ⁹-THC may prevent MMP-8 upregulation by epigenetic mechanisms by maintaining expression of miR-204, a miRNA that directly targets MMP8. Additionally, Δ⁹-THC increased the percentage of CD163⁺ anti-inflammatory macrophages and prevented downregulation of epithelial tight junction protein expression. Collectively, the anti-inflammatory effects of cannabinoids in the intestine may help maintain epithelial barrier integrity and prevent microbial translocation (8).