Nur77作为Paneth细胞分化和功能的新调控因子。
Nur77 as a novel regulator of Paneth cell differentiation and function.
发表日期：2023 Sep 06
作者：
Chenbin Cui, Xinru Wang, Yao Zheng, Lin Wu, Lindeng Li, Hongkui Wei, Jian Peng
来源：
Mucosal Immunology
摘要：
作为肠道先天免疫的一部分，Paneth细胞通过其多种功能在维持肠道稳态方面发挥重要作用。然而，Paneth细胞的调节被证明是复杂而多样的。在这里，我们鉴定了核受体Nur77作为Paneth细胞分化和功能的新调节因子。Nur77缺陷导致小鼠回肠隐窝中的Paneth细胞丧失。具有Nur77缺陷的肠道组织或器官均表现出受损的肠道干细胞（ISC）生态位，并且在Paneth细胞脱颗粒后未能增强抗微生物肽（AMP）的表达。Nur77-/-小鼠中的Paneth细胞和AMP缺陷导致肠道微生物群紊乱。Nur77缺陷使新生小鼠易感于坏死性肠结肠炎（NEC）。机制上，Nur77通过转录抑制Dact1表达以激活Wnt信号通路，从而促进Paneth细胞分化和功能。综上所述，我们的数据提示了Nur77在Paneth细胞分化和功能中的调控作用，并揭示了一种新的Dact1介导的Wnt抑制机制在Paneth细胞发育中的作用。版权所有© 2023 Elsevier Inc.发表。
Serving as a part of intestinal innate immunity, Paneth cells plays an important role in intestinal homeostasis maintenance via their multiple functions. However, the regulation of Paneth cells has been proved to be complex and diverse. Here, we identified nuclear receptor Nur77 as a novel regulator of Paneth cell differentiation and function. Nur77 deficiency led to the loss of Paneth cells in murine ileal crypts. Intestinal tissues or organoids with Nur77 deficiency exhibited the impaired intestinal stem cell (ISC) niche and failed to enhance antimicrobial peptide (AMP) expression after Paneth cell degranulation. The defects in Paneth cells and AMPs in Nur77-/- mice led to intestinal microbiota disorders. Nur77 deficiency rendered postnatal mice susceptible to necrotizing enterocolitis (NEC). Mechanistically, Nur77 transcriptionally inhibited Dact1 expression to activate Wnt signaling activity, thus promoting Paneth cell differentiation and function. Taken together, our data suggest the regulatory role of Nur77 in Paneth cell differentiation and function and reveal a novel Dact1-mediated Wnt inhibition mechanism in Paneth cell development.Copyright © 2023. Published by Elsevier Inc.