Intestinal CXCR6 ILC3s Migrate to the Kidney and Exacerbate Renal Fibrosis Via IL-23 Receptor Signaling Enhanced by PD-1 Expression

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2024 May 30

PMID 38815582

Authors

Zhou Liang

Ziwen Tang

Changjian Zhu

Feng Li

Shuaijiabin Chen

Xu Han

Ruilin Zheng

Xinrong Hu

Ruoni Lin

Qiaoqiao Pei

Changjun Yin

Ji Wang

Ce Tang

Nan Cao

Jincun Zhao

Rong Wang

Xiaoyan Li

Ning Luo

Qiong Wen

Jianwen Yu

Jianbo Li

Xi Xia

Xunhua Zheng

Xin Wang

Naya Huang

Zhong Zhong

Chengqiang Mo

Peisong Chen

Yating Wang

Jinjin Fan

Yun Guo

Haojie Zhong

Jiaqi Liu

Zhenwei Peng

Haiping Mao

Guo-Ping Shi

Joseph V Bonventre

Wei Chen

Yi Zhou

Affiliations

Soon will be listed here.

Abstract

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6 ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.

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References

Wang S, Qu Y, Xia P, Chen Y, Zhu X, Zhang J . Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer. Cell Res. 2020; 30(7):610-622. PMC: 7343789. DOI: 10.1038/s41422-020-0312-y. View

Meijers B, Evenepoel P, Anders H . Intestinal microbiome and fitness in kidney disease. Nat Rev Nephrol. 2019; 15(9):531-545. DOI: 10.1038/s41581-019-0172-1. View

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

Grigg J, Shanmugavadivu A, Regen T, Parkhurst C, Ahmed A, Joseph A . Antigen-presenting innate lymphoid cells orchestrate neuroinflammation. Nature. 2021; 600(7890):707-712. PMC: 8702489. DOI: 10.1038/s41586-021-04136-4. View

Smith T, Heger A, Sudbery I . UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy. Genome Res. 2017; 27(3):491-499. PMC: 5340976. DOI: 10.1101/gr.209601.116. View

Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo T, Sun M . PD-1 regulates KLRG1 group 2 innate lymphoid cells. J Exp Med. 2017; 214(6):1663-1678. PMC: 5461001. DOI: 10.1084/jem.20161653. View

Dalli J, Colas R, Arnardottir H, Serhan C . Vagal Regulation of Group 3 Innate Lymphoid Cells and the Immunoresolvent PCTR1 Controls Infection Resolution. Immunity. 2017; 46(1):92-105. PMC: 5283610. DOI: 10.1016/j.immuni.2016.12.009. View

Hu C, Xu B, Wang X, Wan W, Lu J, Kong D . Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology. 2022; 77(1):48-64. PMC: 9970019. DOI: 10.1002/hep.32449. View

Stavropoulou E, Kantartzi K, Tsigalou C, Konstantinidis T, Romanidou G, Voidarou C . Focus on the Gut-Kidney Axis in Health and Disease. Front Med (Lausanne). 2021; 7:620102. PMC: 7859267. DOI: 10.3389/fmed.2020.620102. View

10.

Bal S, Golebski K, Spits H . Plasticity of innate lymphoid cell subsets. Nat Rev Immunol. 2020; 20(9):552-565. DOI: 10.1038/s41577-020-0282-9. View

11.

Fellstrom B, Barratt J, Cook H, Coppo R, Feehally J, De Fijter J . Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017; 389(10084):2117-2127. DOI: 10.1016/S0140-6736(17)30550-0. View

12.

McMahon H, Boucrot E . Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2011; 12(8):517-33. DOI: 10.1038/nrm3151. View

13.

Soriani A, Stabile H, Gismondi A, Santoni A, Bernardini G . Chemokine regulation of innate lymphoid cell tissue distribution and function. Cytokine Growth Factor Rev. 2018; 42:47-55. DOI: 10.1016/j.cytogfr.2018.02.003. View

14.

Kumar B, Ma W, Miron M, Granot T, Guyer R, Carpenter D . Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep. 2017; 20(12):2921-2934. PMC: 5646692. DOI: 10.1016/j.celrep.2017.08.078. View

15.

Qiu J, Heller J, Guo X, Chen Z, Fish K, Fu Y . The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2011; 36(1):92-104. PMC: 3268875. DOI: 10.1016/j.immuni.2011.11.011. View

16.

Bjorklund A, Forkel M, Picelli S, Konya V, Theorell J, Friberg D . The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016; 17(4):451-60. DOI: 10.1038/ni.3368. View

17.

Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo J, Eberl G . Innate Lymphoid Cells: 10 Years On. Cell. 2018; 174(5):1054-1066. DOI: 10.1016/j.cell.2018.07.017. View

18.

Jacquelot N, Seillet C, Wang M, Pizzolla A, Liao Y, Hediyeh-Zadeh S . Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma. Nat Immunol. 2021; 22(7):851-864. PMC: 7611091. DOI: 10.1038/s41590-021-00943-z. View

19.

Chiossone L, Vivier E . Immune checkpoints on innate lymphoid cells. J Exp Med. 2017; 214(6):1561-1563. PMC: 5461009. DOI: 10.1084/jem.20170763. View

20.

Stack E, Wang C, Roman K, Hoyt C . Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014; 70(1):46-58. DOI: 10.1016/j.ymeth.2014.08.016. View