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Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance

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Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance This information is current as Gao-Yu Liu, Xiao-Hui Deng, Xing Li, Ying-Jiao Cao, of September 24, 2021. Yan-Fang Xing, Pan Zhou, Ai-Hua Lei, Quan Yang, Kai Deng, Hui Zhang and Jie Zhou J Immunol published online 22 May 2020 http://www.jimmunol.org/content/early/2020/05/21/jimmun ol.1901095 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/05/21/jimmunol.190109 Material 5.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 22, 2020, doi:10.4049/jimmunol.1901095 The Journal of Immunology Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance Gao-Yu Liu,*,†,‡,1 Xiao-Hui Deng,*,†,‡,1 Xing Li,x,1 Ying-Jiao Cao,*,†,‡ Yan-Fang Xing,{ Pan Zhou,‡ Ai-Hua Lei,‡,‖ Quan Yang,# Kai Deng,‡ Hui Zhang,‡ and Jie Zhou*,† Group 2 innate lymphoid cells (ILC2s) play an important role in the control of tissue inflammation and homeostasis. However, the role of ILC2s in patients with end-stage renal disease (ESRD) has never been illustrated. In this study, we investigated ILC2s in ESRD patients and their clinical significance. Results showed that the frequencies and absolute numbers of ILC2s, not group 1 innate lymphoid cells or innate lymphoid cell precursors, were significantly elevated in the peripheral blood of ESRD patients when compared with those from healthy donor controls. Moreover, ILC2s from ESRD patients displayed enhanced type 2 cytokine pro- duction and cell proliferation. Plasma from ESRD patients significantly increased ILC2 levels and enhanced their effector function after in vitro treatment. The expression of phosphorylation of STAT5 in ILC2s, as well as the amounts of IL-2 in plasma, were Downloaded from increased in ESRD patients when compared with those from healthy donors. Clinically, ESRD patients with higher ILC2 frequencies displayed lower incidence of infectious complications during a mean of 21 month follow-up study. The proportions of ILC2s were negatively correlated with the prognostic biomarkers of chronic kidney disease, including serum parathyroid hormone, creatinine, and phosphorus, whereas they were positively correlated with serum calcium. These observations indicate that ILC2s may play a protective role in ESRD. The Journal of Immunology, 2020, 205: 000–000. http://www.jimmunol.org/ he global prevalence of chronic kidney disease (CKD) is alterations in the immune system in ESRD patients contribute to their ∼13.4% (1). Around 120 million people in China suffer from enhanced susceptibility to infections (6, 8), the underlying mechanism T it (2). CKD therefore represents a huge health, economic, and of which remains to be fully understood. social burden worldwide. End-stage renal disease (ESRD) is the final Innate lymphoid cells (ILCs) are recently identified innate immune stage of CKD, which is characterized by permanent loss of kidney cells that do not express Ag-specific receptors. Distinct subsets of function and requires dialysis or kidney transplantation to sustain the ILCs use different transcription factors and secret different effector patient’s life (3, 4). ESRD patients displayed increased risk of infec- cytokines, which share high similarity with the corresponding helper tions, and this is the leading complication causing death (5–7). The T lymphocyte subsets (9, 10). However, the responses of ILCs are faster upon exposure to pathogens, tissue damage, or other envi- by guest on September 24, 2021 ronmental stimuli (11). Among the three groups of ILCs identified *Joint Program in Immunology, Department of Internal Medicine, Affiliated Guangzhou (9), group 2 ILCs (ILC2s) have been extensively studied. ILC2s Women and Children’s Medical Center, Zhongshan School of Medicine, Sun Yat-sen † reside in a variety of tissues, including mucosal barriers, fat tissue, University, Guangzhou 510623, China; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Med- liver, skin, kidney, and so on (12–16). It has been demonstrated that ical Sciences, Tianjin Medical University, Tianjin 300070, China; ‡Institute of Human ILC2s play important roles in a variety of physiological or patho- Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; xDepartment of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen logical processes, including but not limited to airway hyperrespon- University, Guangzhou 510630, China; {Department of Nephrology, The Third Affiliated sive inflammation, defense against pathogens, tissue repair, and ‖ Hospital of Guangzhou Medical University, Guangzhou 510150, China; Institute of lipogenesis (10, 17–21). Interestingly, several reports revealed that Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang 421008, China; and #Key Laboratory of Immunology, Sino-French Hoffmann Institute, ILC2s play a beneficial role in the protection against renal injury and School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, the associated pathologies, including acute kidney injury, renal China ischemia-reperfusion injury, and progressive glomerulosclerosis in 1 G.-Y.L., X.-H.D., and X.L. contributed equally to this work. mice (16, 22–25). The therapeutic value of ILC2s is therefore sug- ORCIDs: 0000-0001-9145-4769 (X.L.); 0000-0002-2548-7252 (Q.Y.); 0000-0001- gested in the alleviation of renal diseases. However, the role of 5964-1599 (J.Z.). ILC2s in patients with ESRD has never been investigated. Received for publication September 10, 2019. Accepted for publication April 22, In this study, we evaluated ILC2s in patients with ESRD and further 2020. explored their clinical significance. Results showed that both the level This work was supported by the following grants (to J.Z.): the National Natural Science Foundation of China (81925018 and 81771665), the High-Level Talent and function of ILC2s were significantly elevated in ESRD patients Start-Up Funding of Tianjin Medical University, the Natural Science Foundation of when compared with healthy controls. Further studies indicated that Guangdong (2017B030311014), and the Science and Technology Program of the changes of ILC2s may be caused by certain soluble factors from Guangzhou (201605122045238). the plasma of ESRD patients. Importantly, ILC2s were negatively Address correspondence and reprint requests to Dr. Jie Zhou, Department of Immu- nology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai associated with the development of infections and the prognostic Road, Tianjin 300070, China. E-mail address: [email protected] biomarkers of CKD, indicating their potential protective role in ESRD. The online version of this article contains supplemental material. Abbreviations used in this article: CKD, chronic kidney disease; ESRD, end-stage renal disease; ILC, innate lymphoid cell; ILC1, group 1 ILC; ILC2, group 2 ILC; Materials and Methods ILCP, ILC precursor; Lin2, lineage-negative; MFI, mean fluorescence intensity; Study population PGD2, prostaglandin D2; PTH, parathyroid hormone. In this study, ESRD patients (n = 69) and healthy controls (n = 34) were Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 recruited from the Third Affiliated Hospital of Sun Yat-sen University and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901095 2 ILC2 EXPANSION IN ESRD PATIENTS the Third Affiliated Hospital of Guangzhou Medical University (Guangzhou, Cell culture China) during the period between July 2017 and July 2019. All participants were screened for hepatitis B surface Ag, hepatitis C virus Ab, hepatitis D The ILC2 in vitro culture consisted of the following: equal numbers of virus Ag and Ab, and HIV Ab. Participants who had chronic hepatitis virus ILC2s (500 cells) from the peripheral blood of healthy controls and ESRD infection or other acute infections, were positive for HIV-1, or received patients were cultured with IL-2 (20 ng/ml; PeproTech), IL-7 (20 ng/ml; systemic corticosteroids or immunosuppressive agents were excluded PeproTech), and IL-33 (20 ng/ml; PeproTech) for 3 d, then the supernatants were collected for ELISA. from this study, and all patients met the criteria for ESRD as defined by 2 2 current international guidelines. A written informed consent was ob- The Lin cell culture consisted of the following: Lin cells (100,000 cells tained from all participants and/or their legal guardians at the time of per well) from healthy donors that were cultured with medium containing admission, and
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