Estrogen Receptor ß Activation Inhibits Colitis by Promoting the NLRP6-Mediated Autophagy
Estrogen receptor ß (ERß) and NOD-, LRR- and pyrin domain-containing 6 (NLRP6) are highly expressed in intestinal tissues and reduce intestinal inflammation, but their underlying mechanisms are unclear. We found that ERß and NLRP6 levels were reduced in patients with inflammatory bowel disease (IBD), and that deletion of ERß or NLRP6 was exacerbated colitis in mouse models. We discovered that ERß exerted its anti-inflammatory activity by inducing NLRP6-mediated autophagy. Specifically, ERß directly regulated NLRP6 gene expression and NLRP6 inflammasome activation through genomic and non-genomic effects. NLRP6 directly interacted with multiple autophagy-related proteins (including ULK1, BECN1, ATG5-ATG12-ATG16L1 complex, p62, and PHB2). Autophagy stimulation suppresses the inflammatory response by eliminating excess ERß, NLRP6, ASC, Casp-1, IL-1ß, TNF-a and damaged mitochondria. These findings indicate that ERß-NLRP6-autophagy forms a negative feedback loop to maintain intestinal epithelial cell homeostasis and facilitate tissue repair. Overall design: Colon mRNA profiles of 21-day old wild type (WT) and Esr2-/- mice were generated by deep sequencing, in triplicate, using Illumina GAIIx.