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Delta-9-Tetrahydrocannabinol (THC) Alleviates Inflammation by Modulating Immune Responses in LPS-Induced Murine Inflammation Mode

ABSTRACT: While Δ⁹-Tetrahydrocannabinol (THC), is known for its psychoactive effects, its role in modulating complex innate immune cascades remains poorly defined. In this study, we integrated transcriptomic, cellular, and in vivo approaches to investigate how THC regulates lipopolysaccharide (LPS) induced inflammation. Using human THP-1 monocytic cells, we found that THC independently induces a stress-adaptive transcriptional program upregulating genes associated with the unfolded protein response (UPR) and autophagy pathways while robustly suppressing LPS-induced Type-I interferon stimulated genes (ISGs) and pro-inflammatory cytokines such as IL-1β and TNF-α. These results were corroborated in primary human monocytes, where THC significantly reduced the expression of activation markers CD80, CD83, and CD209. In a murine model of systemic inflammation, chronic THC exposure attenuated the activation of splenic myeloid and T cells. Notably, RNA-seq analysis of brain tissue revealed that THC dampened neuroinflammatory gene expression while promoting pathways linked to neurogenesis and synaptic plasticity. Our findings suggest that THC reprograms innate immune cells toward a metabolically adaptive phenotype that limits excessive activation in both the periphery and the central nervous system. This dual action provides a mechanistic framework for the therapeutic potential of cannabinoids in treating chronic inflammatory and neuroimmune disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328034 | GEO | 2026/08/21

REPOSITORIES: GEO

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Project description:The study describes miRNA expression in colon tissue following delta 9 tetrahydrocannabinol (Δ9-THC) administration to chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms underlying its anti-inflammatory effects, we simultaneously profiled miRNA and mRNA expression in colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) administered either vehicle (VEH/SIV; n=9) or Δ9- tetrahydrocannabinol (THC; THC/SIV; n=8). Relative to controls, differentially expressed miRNAs were ~2 fold higher in VEH/SIV than THC/SIV RMs. Proinflammatory miR-130a, miR-222 and miR-29b, Lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV RMs. Compared to VEH/SIV RMs, 10 miRNAs were significantly upregulated in THC-SIV RMs, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV RMs. Moreover, THC/SIV RMs failed to upregulate proinflammatory miR-21, miR-141 and miR-222 and alpha/beta defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV RMs showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13, keratin-8 (stress protection), PROM1 (epithelial proliferation) and anti-HIV CCL5. Trichrome mason 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 RMs, thus demonstrating the ability of THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that THC suppressed intestinal T cell proliferation/activation (Ki67/HLADR) and exhaustion (PD1) and increased the percentages of anti-inflammatory CD163+ macrophages. Finally, while THC did not affect CD4+ T cell levels, it significantly reduced CD8+ T cell percentages in 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 THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

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Delta-9-Tetrahydrocannabinol (THC) Alleviates Inflammation by Modulating Immune Responses in LPS-Induced Murine Inflammation Mode

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