IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2019 Aug 24

PMID 31440249

Citations 35

Authors

Yuling Shi

Zeyu Chen

Zihan Zhao

Yingyuan Yu

Huayu Fan

Xiaoguang Xu

Xiaolin Bu

Jun Gu

Affiliations

Soon will be listed here.

Abstract

Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4 T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4 T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4 T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.

Citing Articles

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References

Read S, Malmstrom V, Powrie F . Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000; 192(2):295-302. PMC: 2193261. DOI: 10.1084/jem.192.2.295. View

Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S . Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2004; 105(2):735-41. PMC: 1847365. DOI: 10.1182/blood-2003-11-3900. View

Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio Blanco G, Caruso R . Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology. 2005; 128(3):687-94. DOI: 10.1053/j.gastro.2004.12.042. View

Zhou L, Ivanov I, Spolski R, Min R, Shenderov K, Egawa T . IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8(9):967-74. DOI: 10.1038/ni1488. View

Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom T . IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007; 448(7152):484-487. PMC: 3805028. DOI: 10.1038/nature05970. View

Nurieva R, Yang X, Martinez G, Zhang Y, Panopoulos A, Ma L . Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007; 448(7152):480-3. DOI: 10.1038/nature05969. View

Lowes M, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba L, Haider A . Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008; 128(5):1207-11. DOI: 10.1038/sj.jid.5701213. View

Fina D, Sarra M, Fantini M, Rizzo A, Caruso R, Caprioli F . Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008; 134(4):1038-48. DOI: 10.1053/j.gastro.2008.01.041. View

Fantini M, Monteleone G, MacDonald T . IL-21 comes of age as a regulator of effector T cells in the gut. Mucosal Immunol. 2008; 1(2):110-5. DOI: 10.1038/mi.2007.17. View

10.

Spolski R, Kim H, Zhu W, Levy D, Leonard W . IL-21 mediates suppressive effects via its induction of IL-10. J Immunol. 2009; 182(5):2859-67. PMC: 2756221. DOI: 10.4049/jimmunol.0802978. View

11.

Harper E, Guo C, Rizzo H, Lillis J, Kurtz S, Skorcheva I . Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol. 2009; 129(9):2175-83. PMC: 2892172. DOI: 10.1038/jid.2009.65. View

12.

Jang E, Cho S, Park H, Paik D, Kim J, Youn J . A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol. 2009; 182(8):4649-56. DOI: 10.4049/jimmunol.0804350. View

13.

Zhou X, Bailey-Bucktrout S, Jeker L, Penaranda C, Martinez-Llordella M, Ashby M . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009; 10(9):1000-7. PMC: 2729804. DOI: 10.1038/ni.1774. View

14.

Caruso R, Botti E, Sarra M, Esposito M, Stolfi C, Diluvio L . Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med. 2009; 15(9):1013-5. DOI: 10.1038/nm.1995. View

15.

Niu X, He D, Zhang X, Yue T, Li N, Zhang J . IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol. 2010; 71(4):334-41. DOI: 10.1016/j.humimm.2010.01.010. View

16.

Moes N, Rieux-Laucat F, Begue B, Verdier J, Neven B, Patey N . Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology. 2010; 139(3):770-8. DOI: 10.1053/j.gastro.2010.06.006. View

17.

Tzartos J, Craner M, Friese M, Jakobsen K, Newcombe J, Esiri M . IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 2011; 178(2):794-802. PMC: 3032888. DOI: 10.1016/j.ajpath.2010.10.043. View

18.

Bovenschen H, van de Kerkhof P, van Erp P, Woestenenk R, Joosten I, Koenen H . Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 2011; 131(9):1853-60. DOI: 10.1038/jid.2011.139. View

19.

Cai Y, Shen X, Ding C, Qi C, Li K, Li X . Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011; 35(4):596-610. PMC: 3205267. DOI: 10.1016/j.immuni.2011.08.001. View

20.

Van Belle A, de Heusch M, Lemaire M, Hendrickx E, Warnier G, Dunussi-Joannopoulos K . IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J Immunol. 2011; 188(1):462-9. DOI: 10.4049/jimmunol.1102224. View