Cxxc finger protein 1 maintains homeostasis and function of intestinal group 3 innate lymphoid cells with aging

Xin Shen; Xianzhi Gao; Yikai Luo; Qianying Xu; Ying Fan; Shenghui Hong; Zhengwei Huang; Xiaoqian Liu; Qianqian Wang; Zuojia Chen; Di Wang; Linrong Lu; Chuan Wu; Han Liang; Lie Wang

doi:10.1038/s43587-023-00453-7

Cxxc finger protein 1 maintains homeostasis and function of intestinal group 3 innate lymphoid cells with aging

Nat Aging. 2023 Aug;3(8):965-981. doi: 10.1038/s43587-023-00453-7. Epub 2023 Jul 10.

Authors

Xin Shen^#^{1

2

3

4}, Xianzhi Gao^#^{1

3

4

5

6}, Yikai Luo^#^{7

8}, Qianying Xu³, Ying Fan⁹, Shenghui Hong⁹, Zhengwei Huang³, Xiaoqian Liu^{1

3}, Qianqian Wang⁹, Zuojia Chen¹⁰, Di Wang³, Linrong Lu³, Chuan Wu¹¹, Han Liang^{12

13

14}, Lie Wang^{15

16

17

18

19

20}

Affiliations

¹ Institute of Immunology and Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Co-Facility Center, Zhejiang University School of Medicine, Hangzhou, China.
³ Zhejiang University School of Medicine, Hangzhou, China.
⁴ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
⁵ Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
⁷ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Program of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA.
⁹ Laboratory Animal Center, Zhejiang University, Hangzhou, China.
¹⁰ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. chuan.wu@nih.gov.
¹² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. hliang1@mdanderson.org.
¹³ Program of Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA. hliang1@mdanderson.org.
¹⁴ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. hliang1@mdanderson.org.
¹⁵ Institute of Immunology and Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. wanglie@zju.edu.cn.
¹⁶ Zhejiang University School of Medicine, Hangzhou, China. wanglie@zju.edu.cn.
¹⁷ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. wanglie@zju.edu.cn.
¹⁸ Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China. wanglie@zju.edu.cn.
¹⁹ Laboratory Animal Center, Zhejiang University, Hangzhou, China. wanglie@zju.edu.cn.
²⁰ Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China. wanglie@zju.edu.cn.

^# Contributed equally.

PMID: 37429951
DOI: 10.1038/s43587-023-00453-7

Abstract

Aging is accompanied by homeostatic and functional dysregulation of multiple immune cell subsets. Group 3 innate lymphoid cells (ILC3s) constitute a heterogeneous cell population that plays pivotal roles in intestinal immunity. In this study, we found that ILC3s in aged mice exhibited dysregulated homeostasis and function, leading to bacterial and fungal infection susceptibility. Moreover, our data revealed that the enrichment of the H3K4me3 modification in effector genes of aged gut CCR6⁺ ILC3s was specifically decreased compared to young mice counterparts. Disruption of Cxxc finger protein 1 (Cxxc1) activity, a key subunit of H3K4 methyltransferase, in ILC3s led to similar aging-related phenotypes. An integrated analysis revealed Kruppel-like factor 4 (Klf4) as a potential Cxxc1 target. Klf4 overexpression partially restored the differentiation and functional defects seen in both aged and Cxxc1-deficient intestinal CCR6⁺ ILC3s. Therefore, these data suggest that targeting intestinal ILC3s may provide strategies to protect against age-related infections.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Homeostasis / genetics
Immunity, Innate* / genetics
Lymphocytes*
Mice
Trans-Activators / genetics

Substances

Cxxc1 protein, mouse
Trans-Activators