Abstract
Introduction: The chemokine receptor CCR4 is expressed by diverse CD4+ T cell subsets including regulatory T cells (Tregs) but its functional importance for leukocyte recruitment and the relevance of its two corresponding chemokines CCL17 and CCL22 have not been studied in immune-mediated crescentic glomerulonephritis (cGN). Methods: Utilizing the single-cell RNA sequencing (scRNAseq) data in analyzing leukocytes isolated from both human and murine nephritic kidneys, we identified CCL17 as a potential therapeutic target in immune-mediated renal disease. Using a mouse model of murine cGN, we then delineated the effects of targeting CCL17 by neutralizing antibodies and in Ccl17 gene-deficient mice. Results: Unsupervised scRNAseq analyses identified the CCL17-CCR4 axis as a mechanism potentially involved in renal T-cell migration. Analyses of functional kidney impairment and histopathological kidney damage revealed an attenuation of crescentic GN in anti-CCL17 antibody-treated mice which was corroborated using in Ccl17 gene-deficient mice. Immunohistochemical analyses revealed that these changes were accompanied by an affected renal Treg recruitment in both experimental approaches. Conclusion: The chemokine receptor CCR4 and its corresponding chemokine CCL17 are expressed in human and murine cGN and targeting the CCR4-CCL17 axis by neutralizing antibodies as well as Ccl17 gene deficiency led to increased renal Treg recruitment and reduced histological and functional kidney damage in murine cGN.
Journal Section:
Laboratory Investigation: Research Article
References
1.
Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016 May 14;387(10032):2036–48.
2.
Kurts C, Panzer U, Anders HJ, Rees AJ. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol. 2013 Oct;13(10):738–53.
3.
Kitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, et al. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020 Aug 27;6(1):71.
4.
Couser WG. Basic and translational concepts of immune-mediated glomerular diseases. J Am Soc Nephrol. 2012 Mar;23(3):381–99.
5.
Panzer U, Huber TB. Immune-mediated glomerular diseases: new basic concepts and clinical implications. Cell Tissue Res. 2021 Aug;385(2):277–9.
6.
Kitching AR, Hutton HL. The players: cells involved in glomerular disease. Clin J Am Soc Nephrol. 2016 Sep 7;11(9):1664–74.
7.
Krebs CF, Schmidt T, Riedel JH, Panzer U. T helper type 17 cells in immune-mediated glomerular disease. Nat Rev Nephrol. 2017 Oct;13(10):647–59.
8.
Suarez-Fueyo A, Bradley SJ, Klatzmann D, Tsokos GC. T cells and autoimmune kidney disease. Nat Rev Nephrol. 2017 Jun;13(6):329–43.
9.
Riedel JH, Turner JE, Panzer U. T helper cell trafficking in autoimmune kidney diseases. Cell Tissue Res. 2021 Aug;385(2):281–92.
10.
Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol. 2008 Sep;9(9):970–80.
11.
Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014;32:659–702.
12.
Chung AC, Lan HY. Chemokines in renal injury. J Am Soc Nephrol. 2011 May;22(5):802–9.
13.
Turner JE, Paust HJ, Steinmetz OM, Peters A, Riedel JH, Erhardt A, et al. CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. J Am Soc Nephrol. 2010 Jun;21(6):974–85.
14.
Paust HJ, Riedel JH, Krebs CF, Turner JE, Brix SR, Krohn S, et al. CXCR3+ regulatory T cells control TH1 responses in crescentic GN. J Am Soc Nephrol. 2016 Jul;27(7):1933–42.
15.
Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2001 Sep 17;194(6):847–53.
16.
Yoshie O, Matsushima K. CCR4 and its ligands: from bench to bedside. Int Immunol. 2015 Jan;27(1):11–20.
17.
Poppensieker K, Otte DM, Schurmann B, Limmer A, Dresing P, Drews E, et al. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3897–902.
18.
Achuthan A, Cook AD, Lee MC, Saleh R, Khiew HW, Chang MW, et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest. 2016 Sep 1;126(9):3453–66.
19.
Alferink J, Lieberam I, Reindl W, Behrens A, Weiss S, Huser N, et al. Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral dendritic cells contrasts selective absence from the spleen. J Exp Med. 2003 Mar 3;197(5):585–99.
20.
Stutte S, Quast T, Gerbitzki N, Savinko T, Novak N, Reifenberger J, et al. Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc Natl Acad Sci U S A. 2010 May 11;107(19):8736–41.
21.
Weber C, Meiler S, Doring Y, Koch M, Drechsler M, Megens RT, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011 Jul;121(7):2898–910.
22.
Heiseke AF, Faul AC, Lehr HA, Forster I, Schmid RM, Krug AB, et al. CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis. Gastroenterology. 2012 Feb;142(2):335–45.
23.
Khaibullin T, Ivanova V, Martynova E, Cherepnev G, Khabirov F, Granatov E, et al. Elevated levels of proinflammatory cytokines in cerebrospinal fluid of multiple sclerosis patients. Front Immunol. 2017;8:531.
24.
Panzer U, Steinmetz OM, Paust HJ, Meyer-Schwesinger C, Peters A, Turner JE, et al. Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice. J Am Soc Nephrol. 2007 Jul;18(7):2071–84.
25.
Riedel JH, Robben L, Paust HJ, Zhao Y, Asada N, Song N, et al. Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury. JCI Insight. 2023 Jan 10;8(1):e160251.
26.
Paust HJ, Song N, De Feo D, Asada N, Tuzlak S, Zhao Y, et al. CD4(+) T cells produce GM-CSF and drive immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12. Sci Transl Med. 2023 Mar 15;15(687):eadd6137.
27.
Eller K, Weber T, Pruenster M, Wolf AM, Mayer G, Rosenkranz AR, et al. CCR7 deficiency exacerbates injury in acute nephritis due to aberrant localization of regulatory T cells. J Am Soc Nephrol. 2010 Jan;21(1):42–52.
28.
Yamada M, Yagita H, Inoue H, Takanashi T, Matsuda H, Munechika E, et al. Selective accumulation of CCR4+ T lymphocytes into renal tissue of patients with lupus nephritis. Arthritis Rheum. 2002 Mar;46(3):735–40.
29.
Sakai R, Ito M, Yoshimoto K, Chikuma S, Kurasawa T, Kondo T, et al. Tocilizumab monotherapy uncovered the role of the CCL22/17-CCR4(+) Treg axis during remission of crescentic glomerulonephritis. Clin Transl Immunology. 2020;9(11):e1203.
30.
Feng G, Bajpai G, Ma P, Koenig A, Bredemeyer A, Lokshina I, et al. CCL17 aggravates myocardial injury by suppressing recruitment of regulatory T cells. Circulation. 2022 Mar 8;145(10):765–82.
31.
Feng G, Zhu C, Lin CY, Bredemeyer A, Forster I, Kreisel D, et al. CCL17 protects against viral myocarditis by suppressing the recruitment of regulatory T cells. J Am Heart Assoc. 2023 Feb 21;12(4):e028442.
32.
Olkhanud PB, Baatar D, Bodogai M, Hakim F, Gress R, Anderson RL, et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 2009 Jul 15;69(14):5996–6004.
33.
Riedel JH, Paust HJ, Krohn S, Turner JE, Kluger MA, Steinmetz OM, et al. IL-17F promotes tissue injury in autoimmune kidney diseases. J Am Soc Nephrol. 2016 Dec;27(12):3666–77.
34.
Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron. 2013 Aug;6(2):147–57.
35.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004 Sep;10(9):942–9.
36.
Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009 Mar 1;69(5):2000–9.
37.
Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010 Aug 15;127(4):759–67.
38.
Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3 + CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17945–50.
39.
Maeda S, Murakami K, Inoue A, Yonezawa T, Matsuki N. CCR4 blockade depletes regulatory T cells and prolongs survival in a canine model of bladder cancer. Cancer Immunol Res. 2019 Jul;7(7):1175–87.
40.
Broccoli A, Argnani L, Zinzani PL. Peripheral T-cell lymphomas: focusing on novel agents in relapsed and refractory disease. Cancer Treat Rev. 2017 Nov;60:120–9.
41.
Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012 Mar 10;30(8):837–42.
42.
Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol. 2006 Oct 1;177(7):4488–94.
43.
Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, et al. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med. 2007 Jun 11;204(6):1335–47.
44.
Li ZQ, Wang HY, Zeng QL, Yan JY, Hu YS, Li H, et al. p65/miR-23a/CCL22 axis regulated regulatory T cells recruitment in hepatitis B virus positive hepatocellular carcinoma. Cancer Med. 2020 Jan;9(2):711–23.
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