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.

雌激素受体β（Estrogen receptor β，ERβ）与含NOD、LRR及pyrin结构域蛋白6（NOD-, LRR- and pyrin domain-containing 6，NLRP6）在肠道组织中呈高表达状态，可缓解肠道炎症反应，但其具体调控机制尚不明确。本研究发现，炎症性肠病（IBD）患者体内ERβ与NLRP6的表达水平显著下调；在小鼠结肠炎模型中，敲除ERβ或NLRP6会加重结肠炎病症。研究揭示，ERβ可通过诱导NLRP6介导的自噬发挥抗炎活性：具体而言，ERβ可通过基因组效应与非基因组效应，直接调控NLRP6的基因表达及NLRP6炎性小体的激活。NLRP6可直接与多种自噬相关蛋白相互作用，包括ULK1、BECN1、ATG5-ATG12-ATG16L1复合物、p62及PHB2。自噬激活可通过清除过量的ERβ、NLRP6、凋亡相关斑点样蛋白（ASC）、半胱天冬酶-1（Casp-1）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）及受损线粒体，抑制炎症应答。上述研究结果表明，ERβ-NLRP6-自噬通路构成负反馈环路，以维持肠道上皮细胞稳态并促进组织修复。总体实验设计：采用Illumina GAIIx测序平台，对21日龄野生型（WT）及Esr2基因敲除（Esr2-/-）小鼠的结肠组织mRNA进行深度测序，每组设置3次生物学重复。