Mechanisms involved in NLRP6 inflammasome activation. Intestinal microbiota initiate two signals for the activation of the NLRP6 inflammasome. In the first signal, the commensal microbiota serve as a TLR ligand and promotes the transcription of NLRP6 and pro-IL-18. For the second signal, microbial metabolites, including taurine, promote the multiprotein complex assembly to activate the NLRP6 inflammasome. In particular, commensal protozoans promote epithelial IL-18 secretion via activation of the ASC inflammasome. In addition to the microbial roles, CRH inhibits the transcription of NLRP6 inflammasome components, whereas, the nuclear transcription factor PPAR-γ activates NLRP6 by binding to its promoter region. Arrows indicate ‘promotion’, whereas, the symbol ‘┴’ indicates ‘inhibition’. CRH, corticotrophin-releasing hormone; PPAR-γ, peroxisome proliferator-activated receptor-γ; NLRP6, NACHT, LRR and PYD domains-containing protein 6; IL-18, interleukin 18; ASC, apoptosis-associated speck-like protein containing a CARD; TLR, Toll-like receptor.