Nur77 as a novel regulator of Paneth cell differentiation and function

Chenbin Cui; Xinru Wang; Yao Zheng; Lin Wu; Lindeng Li; Hongkui Wei; Jian Peng

doi:10.1016/j.mucimm.2023.09.001

Nur77 as a novel regulator of Paneth cell differentiation and function

Mucosal Immunol. 2023 Sep 6:S1933-0219(23)00067-3. doi: 10.1016/j.mucimm.2023.09.001. Online ahead of print.

Authors

Chenbin Cui¹, Xinru Wang¹, Yao Zheng¹, Lin Wu¹, Lindeng Li¹, Hongkui Wei¹, Jian Peng²

Affiliations

¹ Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan 430070, China.
² Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 400700, China. Electronic address: pengjian@mail.hzau.edu.cn.

PMID: 37683828
DOI: 10.1016/j.mucimm.2023.09.001

Abstract

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.

Keywords: Intestinal microbiota; Intestinal stem cell; Necrotizing enterocolitis; Nur77; Paneth cell differentiation.