Metrnl ameliorates ulcerative colitis by inhibiting NLRP3 inflammasome activation via ASC

Ulcerative colitis (UC) is characterized by the dysregulation of inflammatory pathways, leading to extensive tissue damage and chronic inflammation. NLRP3 inflammasome promotes inflammatory cytokine maturation and pyroptosis. Meteorin-like protein (Metrnl) has anti-inflammatory effects; however, its specific mechanisms in regulating these pathways remain unclear. This study investigated the effect of Metrnl on UC via regulation of the NLRP3 inflammasome through regulation of its key component, apoptosis-associated speck-like protein containing CARD (ASC). NCM460 and FHC cells were treated with TNF-α to establish a cell validation model. Cells with Metrnl interference or overexpression were intervened with three inflammasome activators (ATP, nigericin, or alum), and a caspase-1 inhibitor (belnacasan). The inflammatory factor levels, ASC mRNA and protein expressions, pyroptosis-related proteins, and inflammasome were detected. Interactions between ASC, Metrnl and inflammasome were determined by protein immunoprecipitation. UC models were constructed using wild-type and Metrnl knockout mice. Histopathological changes and differences in pyroptosis-related protein and inflammasome expressions were examined. Metrnl expression was significantly decreased in colitis, and the inflammatory factors IL-1β and LDH expressions increased at the cellular and animal levels, promoting ASC expression and pyroptosis, and activating the inflammasome. Metrnl interference accelerated inflammation and pyroptosis, which were reversed by Metrnl overexpression. Interactive relationships between Metrnl and ASC were noted. Metrnl may mediate ASC protein expression, and reduce IL-1β expression and pyroptosis in colon epithelial cells through the inhibition of ASC-NLRP3 binding. In vivo studies with DSS-induced colitis models confirmed the significance of these findings. After Metrnl knockout, the colon of normal mice was shorter, and Metrnl-/- UC mice showed more severe colon tissue damage, reduced goblet cells, increased inflammation, and accumulation of pyroptosis protein expression, indicating that Metrnl knockout increases susceptibility to UC. Metrnl interferes with key inflammatory signaling pathways in UC by inhibiting the interaction between ASC and NLRP3, suggesting its potential in UC treatment.