Fig. 7

HIV/SIV infection-induced DNA hypomethylation facilitates persistent activation of the NLRP6 sensor and cGAS/MB21D1 protein expression in the intestinal epithelium, leading to epithelial barrier breakdown and microbial translocation (A). Long-term low-dose THC epigenetically modulates these changes by hypermethylating CpG sites in the NLRP6 and cGAS promoters, thereby reducing gastrointestinal mucosal injury (B). NLRP6 inflammasome assembly could potentially activate the RIPK1-RIPK3-MLKL pathway to induce necroptosis of intestinal epithelium (C). TLR3 (Figure S4 K) and NLRP6-DHX15 viral sensing complexes could recognize dsRNA intermediates of HIV, leading to the phosphorylation of RIPK1, which in turn activates RIPK3, culminating in the activation of the necroptosis executioner protein MLKL through phosphorylation on Thr357 and Ser358 (C). Activation of MLKL and concurrent activation of the calcium ion channel TRPM7 enhances intracellular Ca++ influx, leading to necroptotic cell death (D). Cell death facilitates the release and extracellular accumulation of the DAMP protein, HMGB1, which can propagate secondary inflammatory responses by attracting neutrophils and macrophages leading to more widespread epithelial damage (D). By hypermethylating the NLRP6 promoter and increasing expression of the deubiquitinase CYLD, long-term low-dose THC could potentially block the downstream activation of the RIPK1-RIPK3-MLKL pathway and significantly reduce HMGB1 protein expression to attenuate gastrointestinal inflammation and preserve epithelial barrier integrity. Straight and curved arrows denote upregulation or activation, and T-shaped lines indicate inhibition or blockade. Figures were generated using Biorender