Delta-8-tetrahydrocannabinol ameliorates murine autoimmune hepatitis and is associated with epigenetic modulation of immune responses

Functional assays including miRNA mimic/inhibitor transfection and CD4⁺ T-cell differentiation were performed to validate target gene regulation by miRNAs and its role in CD4⁺ T-cell differentiation. Results: Δ⁸-THC markedly suppressed ConA-induced autoimmune hepatitis by restoring immune homeostasis within the liver through suppression of inflammatory monocytes, neutrophils, and natural killer cells, and preservation of tolerogenic Kupffer cells.

In addition, Δ⁸-THC reshaped the hepatic lymphoid compartment, diminishing inflammatory CD4⁺ T-cell responses while favoring regulatory T-cell expansion. These effects were associated with the preservation of miR-100-5p and miR-199a-3p expression in the liver, whereas both miRNAs were markedly downregulated following ConA treatment. mTOR, a central regulator of T-cell differentiation, was identified as a target of these miRNAs.

Consistent with these findings, Δ⁸-THC reduced mTOR expression and upregulated hepatoprotective miRNAs in both in vivo and in vitro models. Functional analyses with miRNA overexpression and inhibition approaches verified the direct regulation of mTOR by these miRNAs in T cells and RAW 264.7 cells. In naïve CD4⁺ T cells, miRNA gain- and loss-of-function experiments demonstrated that miR-100-5p/miR-199a-3p–mediated suppression of mTOR promotes regulatory T-cell differentiation while limiting Th1 and Th17 polarization.

Conclusion: Our results identify Δ⁸-THC as a promising hepatoprotective and anti-inflammatory compound that ameliorates ConA-induced autoimmune hepatitis by influencing CD4+ T-cell differentiation potentially through the miR-100-5p/miR-199a-3p–mTOR axis, highlighting its potential therapeutic value in autoimmune and inflammatory disorders.