Top

Published in:

30-08-2022 | Vulgar Psoriasis | Original Paper

Expression of B lymphocyte-induced maturation protein 1 (Blimp-1) in keratinocyte and cytokine signalling drives human Th17 response in psoriasis

Authors: Lorena Carla Oliveira da Costa, Luiz Gustavo Gardinassi, Flávio Protásio Veras, Cristiane Milanezi, Leandra Náira Zambelli Ramalho, Luciana Benevides, José Carlos Alves-Filho, João Santana da Silva, Cacilda da Silva Souza

Published in: Archives of Dermatological Research | Issue 3/2023

Abstract

Transcriptional factor B lymphocyte-induced maturation protein 1 (Blimp-1) is pivotally implicated in T helper 17 (Th17) cell differentiation. This study investigated expression of the Blimp-1 protein, positive regulatory domain 1 (PRDM1), and cytokine genes in psoriasis (PsO). Affected (AS-PsO) and non-affected skin (nAS-PsO) samples were used to assess gene and protein expressions by reverse transcription-quantitative PCR (RT-qPCR), and immunostaining and confocal microscopy, respectively; the normalised public transcriptomic data permitted differential gene expression analyses. On RT-qPCR, PRDM1 and IL17A transcripts showed higher expression in AS-PsO than in nAS-PsO (n = 34) (p < 0.001; p < 0.0001, respectively). Confocal microscopy showed Blimp-1 protein expression in epidermal layer keratinocytes in AS-PsO, but not in nAS-PsO. Bioinformatic analysis of the transcriptomic dataset GSE13355 corroborated the increased PRDM1, signal transducer and activator of transcription 3 (STAT3), IL12B, TNF, IL17A, IL6, IL1B, IL22, and IL10 gene expression in AS-PsO, when compared to normal skin and nAS-PsO (p < 0.001). PRDM1 expression correlated positively (p < 0.0001) with that of IL17A (r = 0.7), IL1B (r = 0.67), IL12B (r = 0.6), IL6 (r = 0.59), IL22 (r = 0.53), IL23A (r = 0.47), IL21 (r = 0.47), IL27 (r = 0.34), IL23R (r = 0.32), S100 calcium binding protein A9 (r = 0.63), and lipocalin 2 (r = 0.50), and negatively with that of TGFB1 (r = − 0.28) and RORC (r = − 0.60). Blimp-1 may be critical in the pathogenesis of PsO dysregulation involving the Th17 inflammatory pathway. This knowledge may accelerate the development of new treatments.

Available only for authorised users

Teunissen MBM, Koomen CW, de Waal MR et al (1998) Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111:645–649. https://doi.org/10.1046/J.1523-1747.1998.00347.XCrossRefPubMed

Lee E, Trepicchio WL, Oestreicher JL et al (2004) Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199:125–130. https://doi.org/10.1084/JEM.20030451CrossRefPubMedPubMedCentral

Lowes MA, Kikuchi T, Fuentes-Duculan J et al (2008) Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 128:1207–1211. https://doi.org/10.1038/SJ.JID.5701213CrossRefPubMed

Nair RP, Duffin KC, Helms C et al (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genet 41:199–204. https://doi.org/10.1038/ng.311CrossRefPubMedPubMedCentral

Boehncke WH (2015) Etiology and pathogenesis of psoriasis. Rheum Dis Clin N Am 41:665–675. https://doi.org/10.1016/J.RDC.2015.07.013CrossRef

Gottlieb AB, Chamian F, Masud S et al (2005) TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 175:2721–2729. https://doi.org/10.4049/JIMMUNOL.175.4.2721CrossRefPubMed

Cai Y, Xue F, Quan C et al (2019) A critical role of the IL-1β-IL-1R signaling pathway in skin inflammation and psoriasis pathogenesis. J Invest Dermatol 139:146–156. https://doi.org/10.1016/J.JID.2018.07.025CrossRefPubMed

Nograles KE, Zaba LC, Guttman-Yassky E et al (2008) Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159:1092–1102. https://doi.org/10.1111/J.1365-2133.2008.08769.XCrossRefPubMedPubMedCentral

Caruso R, Botti E, Sarra M et al (2009) Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med 15:1013–1015. https://doi.org/10.1038/NM.1995CrossRefPubMed

10.

Chiricozzi A, Romanelli P, Volpe E et al (2018) Scanning the immunopathogenesis of psoriasis. Int J Mol Sci 19:1–31. https://doi.org/10.3390/IJMS19010179CrossRef

11.

Ni X, Lai Y (2020) Keratinocyte: a trigger or an executor of psoriasis? J Leukoc Biol 108:485–491. https://doi.org/10.1002/JLB.5MR0120-439RCrossRefPubMed

12.

Lowes MA, Suárez-Fariñas M, Krueger JG (2014) Immunology of psoriasis. Annu Rev Immunol 32:227–255. https://doi.org/10.1146/ANNUREV-IMMUNOL-032713-120225CrossRefPubMedPubMedCentral

13.

Tsuruta D (2009) NF-kappaB links keratinocytes and lymphocytes in the pathogenesis of psoriasis. Recent Pat Inflamm Allergy Drug Discov 3:40–48. https://doi.org/10.2174/187221309787158399CrossRefPubMed

14.

Ogawa E, Sato Y, Minagawa A, Okuyama R (2018) Pathogenesis of psoriasis and development of treatment. J Dermatol 45:264–272. https://doi.org/10.1111/1346-8138.14139CrossRefPubMed

15.

Goldminz AM, Au SC, Kim N et al (2013) NF-κB: an essential transcription factor in psoriasis. J Dermatol Sci 69:89–94. https://doi.org/10.1016/J.JDERMSCI.2012.11.002CrossRefPubMed

16.

Lynde CW, Poulin Y, Vender R et al (2014) Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 71:141–150. https://doi.org/10.1016/J.JAAD.2013.12.036CrossRefPubMed

17.

Johnson-Huang LM, Lowes MA, Krueger JG (2012) Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech 5:423–433. https://doi.org/10.1242/dmm.009092CrossRefPubMedPubMedCentral

18.

McGeachy MJ, Chen Y, Tato CM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10:314–324. https://doi.org/10.1038/NI.1698CrossRefPubMedPubMedCentral

19.

di Cesare A, di Meglio P, Nestle FO (2009) The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 129:1339–1350. https://doi.org/10.1038/JID.2009.59CrossRefPubMed

20.

Zhang S (2018) The role of transforming growth factor β in T helper 17 differentiation. Immunology 155:24–35. https://doi.org/10.1111/IMM.12938CrossRefPubMedPubMedCentral

21.

Yang L, Anderson DE, Baecher-Allan C et al (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352. https://doi.org/10.1038/NATURE07021CrossRefPubMedPubMedCentral

22.

Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517. https://doi.org/10.1146/annurev.immunol.021908.132710CrossRefPubMed

23.

Bugaut H, Aractingi S (2021) Major Role of the IL17/23 axis in psoriasis supports the development of new targeted therapies. Front Immunol 12:621956. https://doi.org/10.3389/FIMMU.2021.621956CrossRefPubMedPubMedCentral

24.

Keller AD, Maniatis T (1991) Identification and characterization of a novel repressor of-interferon gene expression. Genes Dev 5:868–879. https://doi.org/10.1101/gad.5.5.868CrossRefPubMed

25.

Turner CA, Mack DH, Davis MM (1994) Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77:297–306. https://doi.org/10.1016/0092-8674(94)90321-2CrossRefPubMed

26.

John SA, Garrett-Sinha LA (2009) Blimp1: a conserved transcriptional repressor critical for differentiation of many tissues. Exp Cell Res 315:1077–1084. https://doi.org/10.1016/j.yexcr.2008.11.015CrossRefPubMed

27.

Cimmino L, Martins GA, Liao J et al (2008) Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J Immunol 181:2338–2347. https://doi.org/10.4049/jimmunol.181.4.2338CrossRefPubMed

28.

Johnston RJ, Poholek AC, DiToro D et al (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325:1006–1010. https://doi.org/10.1126/science.1175870CrossRefPubMedPubMedCentral

29.

Cretney E, Xin A, Shi W et al (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12:304–312. https://doi.org/10.1038/NI.2006CrossRefPubMed

30.

Shah N, Guo Y, Wendelsdorf KV et al (2016) A crowdsourcing approach for reusing and meta-analyzing gene expression data. Nat Biotechnol 34:803–806. https://doi.org/10.1038/nbt.3603CrossRefPubMedPubMedCentral

31.

Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340. https://doi.org/10.1038/nrm1619CrossRefPubMed

32.

Magnusdottir E, Kalachikov S, Mizukoshi K et al (2007) Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc Nat Acad Sci USA 104:14988–14993. https://doi.org/10.1073/pnas.0707323104CrossRefPubMedPubMedCentral

33.

Jain R, Chen Y, Kanno Y et al (2016) Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44:131–142. https://doi.org/10.1016/j.immuni.2015.11.009CrossRefPubMed

34.

Lin MH, Yeh LT, Chen SJ et al (2014) T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing Th1 and Th17 cells. Clin Immunol 151:101–113. https://doi.org/10.1016/j.clim.2014.02.006CrossRefPubMed

35.

Lin M-H, Chou F-C, Yeh L-T et al (2013) B lymphocyte-induced maturation protein 1 (BLIMP-1) attenuates autoimmune diabetes in NOD mice by suppressing Th1 and Th17 cells. Diabetologia 56:136–146. https://doi.org/10.1007/s00125-012-2722-yCrossRefPubMed

36.

Salehi S, Bankoti R, Benevides L et al (2012) B lymphocyte—induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17—producing CD4+ T Cells. J Immunol 189:5682–5693. https://doi.org/10.4049/jimmunol.1201966CrossRefPubMed

37.

Fu SH, Yeh LT, Chu CC et al (2017) New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function. J Biomed Sci 24:49. https://doi.org/10.1186/s12929-017-0354-8CrossRefPubMedPubMedCentral

38.

Martins GA, Cimmino L, Shapiro-Shelef M et al (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 7:457–465. https://doi.org/10.1038/ni1320CrossRefPubMed

39.

Chiang MF, Yang SY, Lin IY et al (2013) Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice. Proc Natl Acad Sci U S A 110:6476–6481. https://doi.org/10.1073/pnas.1219462110CrossRefPubMedPubMedCentral

40.

de Sousa AR, Penalva LO, Marcotte EM, Vogel C (2009) Global signatures of protein and mRNA expression levels. Mol Biosyst. https://doi.org/10.1039/b908315dCrossRefPubMedPubMedCentral

41.

Schwanhäusser B, Busse D, Li N et al (2011) Global quantification of mammalian gene expression control. Nature 473:337–342. https://doi.org/10.1038/nature10098CrossRefPubMed

42.

de Jong E, Suddason T, Lord GM (2010) Translational mini-review series on Th17 cells: development of mouse and human T helper 17 cells. Clin Exp Immunol 159:148. https://doi.org/10.1111/J.1365-2249.2009.04041.XCrossRefPubMedPubMedCentral

43.

Ivanov II, McKenzie BS, Zhou L et al (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133. https://doi.org/10.1016/j.cell.2006.07.035CrossRefPubMed

44.

Ivanov II, Zhou L, Littman DR (2007) Transcriptional regulation of Th17 cell differentiation. Sem Immunol 19:409–417. https://doi.org/10.1016/j.smim.2007.10.011CrossRef

45.

Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9:641–649. https://doi.org/10.1038/NI.1610CrossRefPubMedPubMedCentral

46.

Jorn Bovenschen H, van de Kerkhof PC, van Erp PE et al (2011) Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional Skin. J Invest Dermatol 131:1853–1860. https://doi.org/10.1038/jid.2011.139CrossRefPubMed

47.

Korn T, Bettelli E, Gao W et al (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487. https://doi.org/10.1038/nature05970CrossRefPubMedPubMedCentral

48.

Nurieva R, Yang XO, Martinez G et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483. https://doi.org/10.1038/nature05969CrossRefPubMed

49.

Maddur MS, Miossec P, Kaveri SV, Bayry J (2012) Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 181:8–18. https://doi.org/10.1016/j.ajpath.2012.03.044CrossRefPubMed

50.

Shi Y, Chen Z, Zhao Z et al (2019) IL-21 induces an imbalance of Th17/Treg cells in moderate-to-severe plaque psoriasis patients. Front Immunol 10:1865. https://doi.org/10.3389/fimmu.2019.01865CrossRefPubMedPubMedCentral

51.

Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA (2009) Anti-inflammatory and pro-inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 9:447–453. https://doi.org/10.1016/j.coph.2009.04.008CrossRefPubMedPubMedCentral

52.

Fritz Y, Klenotic PA, Swindell WR et al (2017) Induction of alternative proinflammatory cytokines accounts for sustained psoriasiform skin inflammation in IL-17C+IL-6KO mice. J Invest Dermatol 137:696–705. https://doi.org/10.1016/j.jid.2016.10.021CrossRefPubMed

53.

Chang KK, Liu LB, Jin LP et al (2017) IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis. Cell Death Dis 8:e2666. https://doi.org/10.1038/cddis.2017.95CrossRefPubMedPubMedCentral

54.

Stumhofer JS, Silver JS, Laurence A et al (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8:1363–1371. https://doi.org/10.1038/ni1537CrossRefPubMed

55.

Xu J, Yang Y, Qiu G et al (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182:6226–6236. https://doi.org/10.4049/JIMMUNOL.0900123CrossRefPubMed

56.

Neumann C, Heinrich F, Neumann K et al (2014) Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med 211:1807–1819. https://doi.org/10.1084/jem.20131548CrossRefPubMedPubMedCentral

57.

Cretney E, Leung PS, Trezise S et al (2018) Characterization of Blimp-1 function in effector regulatory T cells. J Autoimmunity 91:73–82. https://doi.org/10.1016/j.jaut.2018.04.003CrossRef

58.

Han G, Williams CA, Salter K et al (2010) A role for TGFΒ signaling in the pathogenesis of psoriasis. J Invest Dermatol 130:371–377. https://doi.org/10.1038/jid.2009.252CrossRefPubMed

59.

Flisiak I, Chodynicka B, Porebski P, Flisiak R (2002) Association between psoriasis severity and transforming growth factor β1 and β2 in plasma and scales from psoriatic lesions. Cytokine 19:121–125. https://doi.org/10.1006/cyto.2002.1953CrossRefPubMed

60.

Zaher H, Shaker OG, El-Komy MHM et al (2009) Serum and tissue expression of transforming growth factor beta 1 in psoriasis. J Eur Acad Dermatol Venereol 23:406–409. https://doi.org/10.1111/j.1468-3083.2008.03064.xCrossRefPubMed

61.

Dowlatshahi EA, van der Voort EAM, Arends LR, Nijsten T (2013) Markers of systemic inflammation in psoriasis: a systematic review and meta-analysis. Br J Dermatol 169:266–282. https://doi.org/10.1111/bjd.12355CrossRefPubMed

62.

Isac L, Jiquan S (2019) Interleukin 10 promotor gene polymorphism in the pathogenesis of psoriasis. Acta Dermatovenerol Alp Pannonica Adriat 28:119–123. https://doi.org/10.15570/actaapa.2019.29

Title: Expression of B lymphocyte-induced maturation protein 1 (Blimp-1) in keratinocyte and cytokine signalling drives human Th17 response in psoriasis
Authors: Lorena Carla Oliveira da Costa
Luiz Gustavo Gardinassi
Flávio Protásio Veras
Cristiane Milanezi
Leandra Náira Zambelli Ramalho
Luciana Benevides
José Carlos Alves-Filho
João Santana da Silva
Cacilda da Silva Souza
Publication date: 30-08-2022
Publisher: Springer Berlin Heidelberg
Keywords: Vulgar Psoriasis
Cytokines
Growth Factors
Published in: Archives of Dermatological Research / Issue 3/2023
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI: https://doi.org/10.1007/s00403-022-02379-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression of B lymphocyte-induced maturation protein 1 (Blimp-1) in keratinocyte and cytokine signalling drives human Th17 response in psoriasis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2023

Sentinel lymph node biopsy for head and neck cutaneous squamous cell carcinoma using the Brigham and Women’s staging system: a cost analysis

Nasal reconstructive techniques following Mohs surgery or excisions: a systematic review

Melanoma predilection for the lower limbs of women compared with men

NIH research funding success in dermatology training programs, a cross-sectional analysis

Systematic study on nail plate assessment: differences in nail plate shape, thickness, power Doppler signal and scanning approach

Hidradenitis suppurativa and suicide risk: a multivariate analysis in a disease with a high psychological burden