Δ8-THC—mediated PPARα activation mitigates murine autoimmune hepatitis by suppressing NLRP3 inflammasome Activity and oxidative stress 2259475
TL;DR
Test the hypothesis that Δ8-THC protects against autoimmune hepatitis (AIH) by activating PPARα to suppress inflammasome signaling and oxidative stress and demonstrates that Δ8-THC activates PPARα signaling to inhibit NLRP3 inflammasome activation and ROS production, thereby attenuating liver inflammation and highlighting its potential therapeutic application.
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor highly expressed in liver and immune cells, plays a critical role in mediating anti-inflammatory and antioxidant responses. Aberrant activation of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome and excessive ROS (reactive oxygen species) production are key drivers of hepatic inflammation and tissue injury. The aim of present study was to test the hypothesis that Δ8-THC protects against autoimmune hepatitis (AIH) by activating PPARα to suppress inflammasome signaling and oxidative stress. AIH was induced in C57BL/6 mice by i.v. concanavalin A (ConA, 12.5 mg/kg) and treated i.p. with vehicle or Δ8-THC (20mg/kg). RNA sequencing and Western blot were used to assess NLRP3 inflammasome activation and PPARα expression in hepatic immune cells, while ROS levels were measured using the CellROX assay. Network and functional enrichment analyses identified critical regulators of inflammatory pathways. We found that PPARα expression was markedly reduced in ConA-treated livers. Interestingly, Δ8-THC treatment significantly upregulated hepatic PPARα and suppressed inflammasome-related genes, including NLRP3, caspase-1, and IL-1β, compared to ConA+vehicle treated mice. Moreover, Δ8-THC protected mice from liver injury by reducing ROS accumulation in a dose-dependent manner. The protective effect of Δ8-THC-induced PPARα activation further relied on the suppression of inflammatory mediators including IL-13, IL-23α, IL-15rα, TNFRSF4, TNFRSF9, CXCR1/2, IL-36γ, IL-21, and IFNLR1 induced by ConA. This was further accompanied by downregulation of inflammation-associated hepatic transcripts such as TREM1, GPR84, IFITM6, OLFM4, FPR2, BST1, ADAM8, and S100A8/9. Together, this study demonstrates that Δ8-THC activates PPARα signaling to inhibit NLRP3 inflammasome activation and ROS production, thereby attenuating liver inflammation and highlighting its potential therapeutic application. NIH grants P20GM103641, P30GM154631, R01ES030144, and R01AI160896 Therapeutic Approaches to Autoimmunity (THER)