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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 115-117

Thymic stromal lymphopoietin in dermatological diseases


Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission17-Feb-2019
Date of Decision08-Oct-2019
Date of Acceptance18-Nov-2019
Date of Web Publication18-Aug-2020

Correspondence Address:
Mohamed Ibrahim ElGhareeb
Faculty of Medicine, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_8_19

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  Abstract 


Thymic stromal lymphopoietin is an epithelial cell-derived cytokine expressed in gut, lungs, skin, and thymus. It affects both the local dermal dendritic cells (DCs) and the circulating myeloid DCs. It has important roles in the pathogenesis of many dermatological diseases and may be correlated with disease activity. In this review, its role in the pathogenesis of some dermatological diseases was illustrated.

Keywords: Atopic dermatitis, lichen planus, mycosis fungoides, psoriasis, thymic stromal lymphopoietin


How to cite this article:
ElGhareeb MI. Thymic stromal lymphopoietin in dermatological diseases. Clin Dermatol Rev 2020;4:115-7

How to cite this URL:
ElGhareeb MI. Thymic stromal lymphopoietin in dermatological diseases. Clin Dermatol Rev [serial online] 2020 [cited 2020 Nov 27];4:115-7. Available from: https://www.cdriadvlkn.org/text.asp?2020/4/2/115/292488




  Introduction Top


Thymic stromal lymphopoietin (TSLP) signals through a TSLP receptor (TSLPR), a heterodimer of the interleukin (IL)-7 receptor alpha chain (IL-7Rα) and the TSLPR chain, which is closely related to the common receptor-γ chain and expressed on a wide range of cell types in the adaptive and innate immune system.[1],[2]

The human TSLP gene is located on chromosome 5q22.1 next to the atopic cytokine cluster on 5q31 2. Both mouse and human TSLP exert their biological activities by binding to a heterodimeric receptor that consists of the IL-7 receptor α-chain (IL-7Rα) and the TSLPR chain. TSLPR has low affinity for TSLP, but in combination with IL-7Rα generates a high-affinity binding site for TSLP and triggers the signals.[3]


  Role Of Thymic Stromal Lymphopoietin In Psoriasis Vulgaris Top


IL-23 is a heterodimeric cytokine composed ofp19 (encoded by IL-23A) andp40 (shared with IL-12 and encoded by IL-12B) subunits. The role of IL-23 and its receptor in cutaneous inflammation has been investigated both in mice and humans. Intradermal injection of IL-23 in mice led to erythema, induration, and prominent dermal papillary blood vessels with histopathological features resembling psoriasis.[4] The morphological features of the IL-23-induced skin lesions were more severe than the ones induced by IL-12.[5]

IL-23 activates Th17 cells, stimulating their survival and proliferation, and serves as a key master cytokine regulator in psoriasis. It also seems to be important in the involvement of keratinocytes in inflammation and in the enhancement of Type I immune response in the skin by inducing acanthosis and dermal infiltration by mixed inflammatory cells.[4] IL -23 is also capable of stimulating tumor necrosis factor (TNF)-α expression in macrophages. Psoriasis lesions reveal a significant expression of IL-23 and its receptor. As IL-23 stimulates TNF-α and IL-22, its high expression has been proposed as a causative factor in the onset of psoriasis.[6]

TSLP and TNF-α are epithelium-derived factors able to activate dendritic cells (DCs) and prime for IL-23 production by DCs. TSLP and CD40 L synergistically induced IL-23 production by primary skin DCs compared with stimulation with TSLP or CD40 L alone. Thus, skin DCs behave similarly to blood DCs for TSLP-and CD40 L-induced IL-23 production.[7]

TSLP has already been associated with atopic dermatitis (AD) for its role in inducing a proallergic Th2 response. TSLP is also produced in patients with psoriasis, a Th17- and IL-23-related immune disease. Volpe et al.[8] quantified the in situ TSLP expression in healthy, AD, and psoriatic skin and found comparable levels in patients with two diseases.

Immunohistochemistry revealed that TSLP-specific staining was completely absent in the skin of healthy patients. Importantly, TSLP was highly expressed in the epidermis of patients with psoriasis at similar levels, as seen in AD skin. These results were unexpected as TSLP was formerly described in AD as a Th2 disease, not in a Th1/Th17 disease like psoriasis. These results suggest that TSLP can act in different ways depending on the type of inflammation and propose TSLP as a potential therapeutic target in the treatment of psoriasis.[9]

Volpe et al.[8] found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. Hence, TSLP may act on DCs with two pathways. One through toll-like receptor leading to decrease of IL-12/IL-23 p40 with subsequent Th2 cytokines predominance as in atopic patients. The other pathways through CD40 L that lead to an increase in IL12/1L-23p40 with an increase in IL-23 and predominance of Th17 cytokines as in psoriasis patients.[8],[9]


  Oral Lichen Plans Top


Oral lichen planus (OLP) is a chronic inflammatory disease characterized by the abnormally keratinized oral mucosa and band-like T-cell infiltration in the upper lamina propria. TSLP may enroll in the pathology of OLP, and the TSLP-TSLPR interaction may play an important role in it.[10]

Yamauchi et al.[11] found that the expression of TSLP and CD11c in patients with OLP was significantly higher than control groups, but there was no significant difference between level TSLP expression in the erosive and nonerosive forms.

Importantly, TSLP expression in lichen planus patients was detected mainly in the cell membrane of epithelium keratinocytes, especially in the spinous layers keratinocytes with acanthosis and in the stratum basal keratinocytes associated with the number of mononuclear cells infiltrating in the lamina propria. While in normal controls, only weak TSLP expression in the cytoplasm of epithelium keratinocytes could be found.[12]

Sun et al.[13] hypothesized that TSLP would be released from the cytoplasm to the extracellular under abnormal inflammatory stimulation and associated with the ability of cell proliferation, and hence, TSLP might play an important role in the immunopathology of OLP.


  Atopic Dermatitis Top


TSLP is a possible candidate protein involved in the initiation, development, and progression of atopy and atopic diseases. Human CD11c+ DCs produced CCL17 and CCL22 following exposure to TSLP, which are capable of attracting Th2-type CD4± T-cells.[14] In addition, when naïve CD4+ T cells are exposed to TSLP-treated DCs, they underwent extensive proliferation and differentiation into Th2 lymphocytes and acquired an inflammatory Th2 phenotype, producing IL-4, IL-5, IL-13, and TNF-α on restimulation.[15]

Periostin, an extracellular matrix protein induced by Th2 cytokines, is mainly produced by fibroblasts. Periostin is highly expressed in the skin tissues of patients with AD. Periostin promotes the survival and proliferation of keratinocytes and directly induces the production of TSLPin vitro Thus, periostin acts as a mediator for amplification and chronicity of allergic skin inflammation as occurs in AD through the production of TSLP, which activates various kinds of immune cells, including DCs, to promote Th2-mediated immune responses.[16]


  Cutaneous T-Cell Lymphoma Top


Mycosis fungoides and Sezary syndrome are the most common types of cutaneous T-cell lymphomas (CTCL). Most cases with CTCL, especially at advanced stages, show a Th2-dominant phenotype, characterized by increased IL4, IL5, IL10, and IL13 production. The Th2-dominant environment is beneficial for tumor cells because it undermines interferon-gamma producing Th1 cell antitumor immune responses. TSLP has been reported to impact on various kinds of antigen-presenting cells (APC) such as DCs and monocytes. Specifically, TSLP has been shown to stimulate the expression of Th2 chemokines such as CCL17 by APCs and enhance the maturation of DCs.[17]

TSLP and periostin mRNA levels in CTCL lesional skin were significantly increased.[18] Serum TSLP levels in CTCL patients were higher than those in normal controls. These results suggest that TSLP play an important role in creating a Th2-dominant environment in CTCL, as has been reported in AD.[19]


  Conclusion Top


  • TSLP is a cytokine that may act on DCs with two pathways. One through toll-like receptor leading to decrease of IL-12/IL-23 p40 with subsequent Th2 cytokines predominance as in atopic patients. The other pathways through CD40 L that leads to an increase in IL12/1L-23p40 with an increase in IL-23 and predominance of Th17 cytokines as in psoriasis patients
  • What direct TSLP to go in one of these two pathways may be the genetic background of the patient or the type of TSLP as long isoform of TSLP is biased to CD40 L with the increase in IL-23 and the development of psoriasis
  • TSLP might play an important role in the immunopathology of OLP
  • TSLP plays an important role in creating a Th2-dominant environment in CTCL and Sezary syndrome.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Okayama Y, Okumura S, Sagara H, Yuki K, Sasaki T, Watanabe N, et al. FcepsilonRI-mediated thymic stromal lymphopoietin production by interleukin-4-primed human mast cells. Eur Respir J 2009;34:425-35.  Back to cited text no. 1
    
2.
Butt J. Effects of An Anti TSLP Antibody on Allergen-Induced Asthmatic. Health & Medicine; 2015.  Back to cited text no. 2
    
3.
Park LS, Martin U, Garka K, Gliniak B, Di Santo JP, Muller W, et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med 2000;192:659-70.  Back to cited text no. 3
    
4.
Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006;203:2577-87.  Back to cited text no. 4
    
5.
Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007;445:648-51.  Back to cited text no. 5
    
6.
Ohta Y, Hamada Y. In situ expression of CD40 and CD40 ligand in psoriasis. Dermatology 2004;209:21-8.  Back to cited text no. 6
    
7.
Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol 2008;181:7420-7.  Back to cited text no. 7
    
8.
Volpe E, Pattarini L, Martinez-Cingolani C, Meller S, Donnadieu MH, Bogiatzi SI, et al. Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis. J Allergy Clin Immunol 2014;134:373-81.  Back to cited text no. 8
    
9.
Tsilingiri K, Fornasa G, Rescigno M. Thymic stromal lymphopoietin: To cut a long story short. Cell Mol Gastroenterol Hepatol 2017;3:174-82.  Back to cited text no. 9
    
10.
Wang H, Zhang D, Han Q, Zhao X, Zeng X, Xu Y, et al. Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus. J Oral Pathol Med 2016;45:385-93.  Back to cited text no. 10
    
11.
Yamauchi M, Moriyama M, Hayashida JN, Maehara T, Ishiguro N, Kubota K, et al. Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus. PLoS One 2017;12:e0173017.  Back to cited text no. 11
    
12.
Sugiura K. The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-of-function variants. J Dermatol Sci 2014;74:187-92.  Back to cited text no. 12
    
13.
Sun M, Tan W, Liu S, Liu G, Zhang X, Wang N, et al. In situ expression and serum level of thymic stromal lymphopoietin in oral lichen planus. J Oral Pathol Med 2014;43:740-5.  Back to cited text no. 13
    
14.
Arima K, Watanabe N, Hanabuchi S, Chang M, Sun SC, Liu YJ. Distinct signal codes generate dendritic cell functional plasticity. Sci Signal 2010;3:ra4.  Back to cited text no. 14
    
15.
Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673-80.  Back to cited text no. 15
    
16.
Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol 2012;129:104-10.  Back to cited text no. 16
    
17.
Miyagaki T, Sugaya M, Fujita H, Ohmatsu H, Kakinuma T, Kadono T, et al. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Invest Dermatol 2010;130:2304-11.  Back to cited text no. 17
    
18.
Ziegler SF. Thymic stromal lymphopoietin and allergic disease. J Allergy Clin Immunol 2012;130:845-52.  Back to cited text no. 18
    
19.
Takahashi N, Sugaya M, Suga H, Oka T, Kawaguchi M, Miyagaki T, et al. Thymic Stromal Chemokine TSLP Acts through Th2 Cytokine Production to Induce Cutaneous T-cell Lymphoma. Cancer Res 2016;76:6241-52.  Back to cited text no. 19
    




 

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  In this article
Abstract
Introduction
Role Of Thymic S...
Oral Lichen Plans
Atopic Dermatitis
Cutaneous T-Cell...
Conclusion
References

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