Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis

Wu, Di1; Li, Zongxian1; Zhang, Yime1; Zhang, Yinlian1; Ren, Guanqun1; Zeng, Yanyu1; Liu, Huiying2; Guan, Weiqiang3; Zhao, Xingyu1; Li, Peng1; Hu, Luni1; Hou, Zhiyuan4; Gong, Jingjing4; Li, Jun5; Jin, Wenfei6; Hu, Zeping7; Jiang, Changtao2; Li, Houhua3; Zhong, Chao1

2023-10-01

10.1038/s42255-023-00908-6

NATURE METABOLISM   Impact Factor & Quartile

2522-5812

Metabolic regulation is integral to the proper functioning of innate lymphoid cells, yet the underlying mechanisms remain elusive. Here, we show that disruption of exogenous proline uptake, either through dietary restriction or by deficiency of the proline transporter Slc6a7, in lymphoid tissue inducer (LTi) cells, impairs LTi activation and aggravates dextran sodium sulfate-induced colitis in mice. With an integrative transcriptomic and metabolomic analysis, we profile the metabolic characteristics of various innate lymphoid cell subsets and reveal a notable enrichment of proline metabolism in LTi cells. Mechanistically, defective proline uptake diminishes the generation of reactive oxygen species, previously known to facilitate LTi activation. Additionally, LTi cells deficient in Slc6a7 display downregulation of Cebpb and Kdm6b, resulting in compromised transcriptional and epigenetic regulation of interleukin-22. Furthermore, our study uncovers the therapeutic potential of proline supplementation in alleviating colitis. Therefore, these findings shed light on the role of proline in facilitating LTi activation and ultimately contributing to gut homeostasis.

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We thank members of the Zhong groups for inspiring discussion and all contributions. Additionally, we thank the Mass Spectrometry Core Facility of School of Basic Medicines, Peking University Health Science Center for their support on metabolomic analysis.["32170896","31770957","91842102"] ; National Natural Science Foundation of China["2022YFA0806400","2022YFA1103602"] ; National Key Research amp; Development Program of China[18G10645] ; Natural Science Foundation of Beijing[JCYJ20220818100401003] ; Shenzhen Innovation Committee of Science and Technology[2023T160031]

Endocrinology & Metabolism

Endocrinology & Metabolism

WOS:001085952300003

NATURE PORTFOLIO

Web of Science

1.Peking Univ, NHC Key Lab Med Immunol, Beijing Key Lab Tumor Syst Biol, Inst Syst Biomed,Dept Immunol,Hlth Sci Ctr, Beijing, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China
3.Peking Univ, Chem Biol Ctr, Hlth Sci Ctr, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Inst Syst Biomed, Beijing, Peoples R China
5.Peking Univ Third Hosp, Dept Gastroenterol, Beijing, Peoples R China
6.Southern Univ Sci & Technol, Sch Life Sci, Dept Biol, Shenzhen, Peoples R China
7.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing Frontier Res Ctr Biol Struct, Sch Pharmaceut Sci, Beijing 100084, Peoples R China

Wu, Di,Li, Zongxian,Zhang, Yime,et al. Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis[J]. NATURE METABOLISM,2023.

Wu, Di.,Li, Zongxian.,Zhang, Yime.,Zhang, Yinlian.,Ren, Guanqun.,...&Zhong, Chao.(2023).Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis.NATURE METABOLISM.

Wu, Di,et al."Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis".NATURE METABOLISM (2023).