TSLP and asthma: fellow travelers

Abstract

The incidence of asthma, a heterogeneous inflammatory disease affecting over 300 million people worldwide, continues to increase in developed countries. Human epithelial cells (ECs) express the alarmin-type cytokine thymic stromal lymphopoietin (TSLP) following tissue injury triggered by several environmental insults, which include allergens, smoke, pollutants, or other irritants. Furthermore, TSLP has an emerging but well-documented pathogenic role in asthma. TSLP has been called a “master switch” of allergic inflammation at the epithelial-dendritic cell (DC) interface, where it supports T helper 2 (Th2) inflammatory polarization and promotes the maintenance of Th2 memory responses. Therefore, targeting TSLP/TSLP-mediated signaling may represent an attractive therapeutic strategy for asthma. Several studies of anti-TSLP drugs are ongoing; the first-in-class anti-TSLP monoclonal antibody (mAb) tezepelumab, the immunoglobulin G1 antibody fragment CSJ117, or TSLP-traps [a combination of anti-interleukin-13 (anti-IL-13) and anti-TSLP mAbs] all represent promising new treatment approaches. This article reviews the characteristics of TSLP and discusses the treatment of severe asthma through TSLP-associated mechanisms.

Keywords

Asthma / thymic stromal lymphopoietin (TSLP) / alarmin

References

[1] Ebert CS Jr, Pillsbury HC 3rd. Epidemiology of allergy. Otolaryngol Clin North Am. 2011; 44: 537-48.

[2] Menzies-Gow A, Wechsler ME, Brightling CE. Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option? Respir Res. 2020; 21: 268.

[3] Zhang K, Feng Y, Liang Y, Wu W, Chang C, Chen D, et al. Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2-high asthma. JCI Insight. 2021; 6: e148103.

[4] Yi L, Cheng D, Zhang K, Huo X, Mo Y, Shi H, et al. Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis. Mucosal Immunol. 2017; 10: 1491-503.

[5] Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-Stec EM, Hartnett C, et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003; 9: 47-52.

[6] Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019; 20: 1603-9.

[7] Mitchell PD, O’Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017; 151: 1338-44.

[8] Bauer T, Gubi D, Klufa J, Novoszel P, Holcmann M, Sibilia M. Ex-vivo skin explant culture is a model for TSLP-mediated skin barrier immunity . Life (Basel). 2021; 11: 1237.

[9] Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ. A role for TSLP in the development of inflammation in an asthma model. J Exp Med. 2005; 202: 829-39.

[10] Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005; 174: 8183-90.

[11] 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.

[12] Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010; 42: 289-91.

[13] Demehri S, Morimoto M, Holtzman MJ, Kopan R. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009; 7: e1000067.

[14] Han H, Xu W, Headley MB, Jessup HK, Lee KS, Omori M, et al. Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma. Mucosal Immunol. 2012; 5: 342-51.

[15] Fang Mercado L, Martinez Alfaro B, Marrugo Cano J. Thymic stromal lymphopoietin and its relationship with allergic diseases. Ciencia y Salud Virtual. 2015; 7: 59-70. Spanish.

[16] Sebastian K, Borowski A, Kuepper M, Friedrich K . Signal transduction around thymic stromal lymphopoietin (TSLP) in atopic asthma. Cell Commun Signal. 2008; 6: 5.

[17] Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005; 6: 1047-53.

[18] Hirose K, Iwata A, Tamachi T, Nakajima H. Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev. 2017; 278: 145-61.

[19] van Heerden D, van Binnendijk RS, Tromp SAM, Savelkoul HFJ, van Neerven RJJ, den Hartog G. Asthma-associated long TSLP inhibits the production of IgA. Int J Mol Sci. 2021; 22: 3592.

[20] Parmar A. Thymic stromal lymphopoietin and its downstream networks in severe asthma [dissertation]. Leicester: University of Leicester; 2013.

[21] Mitchell PD, O’Byrne PM. Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma. Pharmacol Ther. 2017; 169: 104-12.

[22] Wang W, Li Y, Lv Z, Chen Y, Li Y, Huang K, et al. Bronchial allergen challenge of patients with atopic asthma triggers an alarmin (IL-33, TSLP, and IL-25) response in the airways epithelium and submucosa. J Immunol. 2018; 201: 2221-31.

[23] Nguyen KD, Vanichsarn C, Nadeau KC. TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin Immunol. 2010; 6: 4.

[24] West EE, Kashyap M, Leonard WJ. TSLP: a key regulator of asthma pathogenesis. Drug Discov Today Dis Mech. 2012; 9: e83-8.

[25] Ukleja-Sokołowska N, Żbikowska-Gotz M, Lis K, Adamczak R, Bartuzi Ż. Assessment of TSLP, IL 25 and IL 33 in patients with shrimp allergy. Allergy Asthma Clin Immunol. 2021; 17: 76.

[26] Komai M, Tanaka H, Masuda T, Nagao K, Ishizaki M, Sawada M, et al. Role of Th2 responses in the development of allergen-induced airway remodelling in a murine model of allergic asthma. Br J Pharmacol. 2003; 138: 912-20.

[27] Wu J, Dong F, Wang RA, Wang J, Zhao J, Yang M, et al. Central role of cellular senescence in TSLP-induced airway remodeling in asthma. PLoS One. 2013; 8: e77795.

[28] Chen ZG, Zhang TT, Li HT, Chen FH, Zou XL, Ji JZ, et al. Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite. PLoS One. 2013; 8: e51268.

[29] Chen YL, Chiang BL. Targeting TSLP with shRNA alleviates airway inflammation and decreases epithelial CCL17 in a murine model of asthma. Mol Ther Nucleic Acids. 2016; 5: e316.

[30] Bunyavanich S, Melen E, Wilk JB, Granada M, Soto-Quiros ME, Avila L, et al. Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma . Clin Mol Allergy. 2011; 9: 1.

[31] Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017; 377: 936-46. Erratum in: N Engl J Med. 2019;380:2082.

[32] Pham TH, Ren P, Parnes JR, Griffiths JM. Tezepelumab reduces multiple key inflammatory biomarkers in patients with severe, uncontrolled asthma in the phase 2b PATHWAY study. AJRCCM. 2019; 199: A2677.

[33] Corren J, Chen S, Callan L, Gil EG. The impact of tezepelumab on hospitalization and emergency department visits in patients with severe uncontrolled asthma: results from the pathway phase 2b trial. AJRCCM. 2019; 199: A2622.

[34] Ly N, Zheng Y, Griffiths JM, van der Merwe R, Agoram B, Parnes JR, et al. Pharmacokinetic and pharmacodynamic modeling of tezepelumab to guide phase 3 dose selection for patients with severe asthma. J Clin Pharmacol. 2021; 61: 901-12.

[35] Matera MG, Rogliani P, Calzetta L, Cazzola M. TSLP inhibitors for asthma: current status and future prospects. Drugs. 2020; 80: 449-58.

[36] Global strategy for asthma management and prevention [Internet]. Fontana: Global Initiative for Asthma; [cited 2022 Nov 23]. Available from: https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf