Targeting thymic stromal lymphopoietin in nasal type 2 inflammation

Abstract

Epithelial cell-derived thymic stromal lymphopoietin (TSLP) plays a crucial role in mediating type 2 immune responses, which is one of the key underlying patho-physiological mechanisms of allergic rhinitis (AR) and most presentations of chronic rhinosinusitis with nasal polyps (CRSwNP). Researches show that inhibiting TSLP signaling has significant therapeutic potential in alleviating type 2 inflammation. Biologics targeting TSLP have been developed and introduced into clinical practice, yielding promising therapeutic outcomes, especially in asthma. Several anti-TSLP antibodies are undergoing clinical trials to investigate the efficacy and safety in treating CRSwNP and AR. This review aims to delve into the latest progress regarding the functional role of TSLP, the clinical outcomes associated with antiTSLP therapies, and the therapeutic potential of anti-TSLP antibodies in treating nasal type 2 inflammation.

Keywords

allergic rhinitis / biologics / chronic rhinosinusitis with nasal polyps / thymic stromal lymphopoietin / type 2 inflammation

References

[1] Fokkens WJ , Lund VJ , Hopkins C , et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020; 58 (suppl S29): 1- 464.

[2] Wang M , Wang C , Akdis CA , Zhang L . The highly prevalent allergic rhinitis: does new treatments move toward a cure? Sci Bull. 2023; 68 (24): 3094- 3097.

[3] Passali D , Cingi C , Staffa P , Passali F , Muluk NB , Bellussi ML . The International Study of the Allergic Rhinitis Survey: outcomes from 4 geographical regions. Asia Pac Allergy. 2018; 8 (1): e7.

[4] Min HK , Lee S , Kim S . Global incidence and prevalence of chronic rhinosinusitis: a systematic review. Clin Exp Allergy. 2025; 55 (1): 52- 66.

[5] Zhang L , Zhang R , Pang K , Liao J , Liao C , Tian L . Prevalence and risk factors of chronic rhinosinusitis among Chinese: a systematic review and meta-analysis. Front Public Health. 2022; 10: 986026.

[6] Dykewicz MS , Wallace DV , Amrol DJ . Rhinitis 2020: a practice parameter update. J Allergy Clin Immunol. 2020; 146 (4): 721- 767.

[7] Shah SA , Kobayashi M . Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype. Heliyon. 2023; 9 (9): e19249.

[8] Bachert C , Bhattacharyya N , Desrosiers M , Khan AH . Burden of disease in chronic rhinosinusitis with nasal polyps. J Asthma Allergy. 2021; 14: 127- 134.

[9] Ogulur I , Pat Y , Ardicli O . Advances and highlights in biomarkers of allergic diseases. Allergy. 2021; 76 (12): 3659- 3686.

[10] Pelaia C , Pelaia G , Maglio A . Pathobiology of type 2 inflammation in asthma and nasal polyposis. J Clin Med. 2023; 12 (10): 3371.

[11] Benjamin MR , Stevens WW , Li N . Clinical characteristics of patients with chronic rhinosinusitis without nasal polyps in an academic setting. J Allergy Clin Immunol Pract. 2019; 7 (3): 1010- 1016.

[12] Zhu Z , Zhao C , Wang M . IL-4/IL-13 pathway in nasal type 2 inflammation: the central role and targeted therapy. Eye & ENT Research. 2024; 1 (1): 39- 48.

[13] Hong H , Liao S , Chen F , Yang Q , Wang DY . Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. Allergy. 2020; 75 (11): 2794- 2804.

[14] An G , Wang W , Zhang X . Combined blockade of IL-25, IL-33 and TSLP mediates amplified inhibition of airway inflammation and remodelling in a murine model of asthma. Respirology. 2020; 25 (6): 603- 612.

[15] Ebina-Shibuya R , Leonard WJ . Role of thymic stromal lymphopoietin in allergy and beyond. Nat Rev Immunol. 2023; 23 (1): 24- 37.

[16] Ogasawara N , Klingler AI , Tan BK . Epithelial activators of type 2 inflammation: elevation of thymic stromal lymphopoietin, but not IL-25 or IL-33, in chronic rhinosinusitis with nasal polyps in Chicago, Illinois. Allergy. 2018; 73 (11): 2251- 2254.

[17] Bunyavanich S , Melen E , Wilk JB . Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma. Clin Mol Allergy. 2011; 9: 1.

[18] Yu SE , Olonisakin TF , Moore JA , Chiang S , Lee SE . The Association of TSLP and IL-4 with patient-reported outcome measures in chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2025; 39 (2): 118- 127.

[19] Liao B , Cao PP , Zeng M . Interaction of thymic stromal lymphopoietin, IL-33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps. Allergy. 2015; 70 (9): 1169- 1180.

[20] Kimura S , Pawankar R , Mori S . Increased expression and role of thymic stromal lymphopoietin in nasal polyposis. Allergy Asthma Immunol Res. 2011; 3 (3): 186- 193.

[21] Kurihara M , Kabata H , Irie M , Fukunaga K . Current summary of clinical studies on anti-TSLP antibody, Tezepelumab, in asthma. Allergol Int. 2023; 72 (1): 24- 30.

[22] Pelaia C , Crimi C , Vatrella A , Tinello C , Terracciano R , Pelaia G . Molecular targets for biological therapies of severe asthma. Front Immunol. 2020; 11: 603312.

[23] Friend SL , Hosier S , Nelson A , Foxworthe D , Williams DE , Farr A . A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp Hematol. 1994; 22 (3): 321- 328.

[24] Fornasa G , Tsilingiri K , Caprioli F . Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. J Allergy Clin Immunol. 2015; 136 (2): 413- 422.

[25] Zhao J , Zhang J , Tang S . The different functions of short and long thymic stromal lymphopoietin isoforms in autophagymediated asthmatic airway inflammation and remodeling. Immunobiology. 2021; 226 (5): 152124.

[26] Gauvreau GM , Sehmi R , Ambrose CS , Griffiths JM . Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets. 2020; 24 (8): 777- 792.

[27] Canè L , Poto R , Palestra F . Thymic stromal lymphopoietin (TSLP) is cleaved by human mast cell tryptase and chymase. Int J Mol Sci. 2024; 25 (7): 4049.

[28] Smolinska S , Antolín-Amérigo D , Popescu FD , Jutel M . Thymic stromal lymphopoietin (TSLP), its isoforms and the interplay with the epithelium in allergy and asthma. Int J Mol Sci. 2023; 24 (16): 12725.

[29] Theofani E , Tsitsopoulou A , Morianos I , Semitekolou M . Severe asthmatic responses: the impact of TSLP. Int J Mol Sci. 2023; 24 (8): 7581.

[30] Guttman-Yassky E , Irvine AD , Brunner PM . The role of Janus kinase signaling in the pathology of atopic dermatitis. J Allergy Clin Immunol. 2023; 152 (6): 1394- 1404.

[31] Hu X , Li J , Fu M , Zhao X , Wang W . The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Targeted Ther. 2021; 6 (1): 402.

[32] Wang Y , Cao Z , Zhao H , Gu Z . Nonylphenol exacerbates ovalbumin-induced allergic rhinitis via the TSLP-TSLPR/IL-7R pathway and JAK1/2-STAT3 signaling in a mouse model. Ecotoxicol Environ Saf. 2022; 243: 114005.

[33] Kim M , Yuk HJ , Min Y , Kim DS , Sung YY . Securinega suffruticosa extract alleviates atopy-like lesions in NC/Nga mice via inhibition of the JAK1-STAT1/3 pathway. Biomed Pharmacother. 2023; 169: 115903.

[34] Zhou C , Wang P , Lei L , Huang Y , Wu Y . Overexpression of miR-142-5p inhibits the progression of nonalcoholic steatohepatitis by targeting TSLP and inhibiting JAK-STAT signaling pathway. Aging (Albany NY). 2020; 12 (10): 9066- 9084.

[35] Wong CK , Hu S , Cheung PF , Lam CW . Thymic stromal lympho-poietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am J Respir Cell Mol Biol. 2010; 43 (3): 305- 315.

[36] Zhong Y , Li Y , Xiao X . The relationship of the expression of thymic stromal lymphopoietin in nasal polyps tissues and Th2 inflammatory response. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014; 28 (11): 817- 820.

[37] Frey A , Lunding LP , Wegmann M . The dual role of the airway epithelium in asthma: active barrier and regulator of inflammation. Cells. 2023; 12 (18): 2208.

[38] Boonpiyathad T , Sözener ZC , Satitsuksanoa P , Akdis CA . Immunologic mechanisms in asthma. Semin Immunol. 2019; 46: 101333.

[39] Wang M , Tan G , Eljaszewicz A . Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells. J Allergy Clin Immunol. 2019; 143 (5): 1892- 1903.

[40] Marković I , Savvides SN . Modulation of signaling mediated by TSLP and IL-7 in inflammation, autoimmune diseases, and cancer. Front Immunol. 2020; 11: 1557.

[41] Wang W , Xu Y , Wang L . Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis. Nat Immunol. 2022; 23 (10): 1484- 1494.

[42] Kabata H , Flamar AL , Mahlakõiv T . Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation. Mucosal Immunol. 2020; 13 (4): 626- 636.

[43] Morianos I , Semitekolou M . Dendritic cells: critical regulators of allergic asthma. Int J Mol Sci. 2020; 21 (21): 7930.

[44] Phan V , Ito T , Inaba M . Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses. Blood Adv. 2020; 4 (15): 3572- 3585.

[45] Hoffmann C , Noel F , Grandclaudon M . PD-L1 and ICOSL discriminate human Secretory and helper dendritic cells in cancer, allergy and autoimmunity. Nat Commun. 2022; 13 (1): 1983.

[46] Gu C , Upchurch K , Horton J . Dectin-1 controls TSLP-induced Th2 response by regulating STAT3, STAT6, and p50-RelB activities in dendritic cells. Front Immunol. 2021; 12: 678036.

[47] Wang SH , Zuo YG . Thymic stromal lymphopoietin in cutaneous immune-mediated diseases. Front Immunol. 2021; 12: 698522.

[48] Nakajima S , Kabata H , Kabashima K , Asano K . Anti-TSLP antibodies: targeting a master regulator of type 2 immune responses. Allergol Int. 2020; 69 (2): 197- 203.

[49] Tatsuno K , Fujiyama T , Yamaguchi H , Waki M , Tokura Y . TSLP directly interacts with skin-homing Th2 cells highly expressing its receptor to enhance IL-4 production in atopic dermatitis. J Invest Dermatol. 2015; 135 (12): 3017- 3024.

[50] Diver S , Khalfaoui L , Emson C . Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE):a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021; 9 (11): 1299- 1312.

[51] Kitajima M , Kubo M , Ziegler SF , Suzuki H . Critical role of TSLP receptor on CD4 T cells for exacerbation of skin inflammation. J Immunol. 2020; 205 (1): 27- 35.

[52] Ochiai S , Jagot F , Kyle RL . Thymic stromal lymphopoietin drives the development of IL-13(+) Th2 cells. Proc Natl Acad Sci U S A. 2018; 115 (5): 1033- 1038.

[53] Rochman Y , Dienger-Stambaugh K , Richgels PK . TSLP signaling in CD4(+) T cells programs a pathogenic T helper 2 cell state. Sci Signal. 2018; 11 (521): eaam8858.

[54] Lai JF , Thompson LJ , Ziegler SF . TSLP drives acute T(H)2-cell differentiation in lungs. J Allergy Clin Immunol. 2020; 146 (6): 1406- 1418.e7.

[55] Kabata H , Moro K , Koyasu S . The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms. Immunol Rev. 2018; 286 (1): 37- 52.

[56] Duerr CU , Fritz JH . Regulation of group 2 innate lymphoid cells. Cytokine. 2016; 87: 1- 8.

[57] Stevens WW , Kato A . Group 2 innate lymphoid cells in nasal polyposis. Ann Allergy Asthma Immunol. 2021; 126 (2): 110- 117.

[58] Toki S , Goleniewska K , Zhang J . TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation. Allergy. 2020; 75 (7): 1606- 1617.

[59] Ji T , Li H . T-helper cells and their cytokines in pathogenesis and treatment of asthma. Front Immunol. 2023; 14: 1149203.

[60] Wirtz S , Schulz-Kuhnt A , Neurath MF , Atreya I . Functional contribution and targeted migration of group-2 innate lymphoid cells in inflammatory lung diseases: being at the right place at the right time. Front Immunol. 2021; 12: 688879.

[61] León B , Ballesteros-Tato A . Modulating Th2 cell immunity for the treatment of asthma. Front Immunol. 2021; 12: 637948.

[62] Ryu G , Kim DW . Th2 inflammatory responses in the development of nasal polyps and chronic rhinosinusitis. Curr Opin Allergy Clin Immunol. 2020; 20 (1): 1- 8.

[63] Bernstein JS , Wechsler ME . Eosinophilic respiratory disorders and the impact of biologics. Curr Opin Pulm Med. 2023; 29 (3): 202- 208.

[64] Reche PA , Soumelis V , Gorman DM . Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J Immunol. 2001; 167 (1): 336- 343.

[65] He R , Geha RS . Thymic stromal lymphopoietin. Ann N Y Acad Sci. 2010; 1183 (1): 13- 24.

[66] Yoou MS , Kim HM , Jeong HJ . Acteoside attenuates TSLP-induced mast cell proliferation via down-regulating MDM2. Int Immunopharmacol. 2015; 26 (1): 23- 29.

[67] Babina M , Wang Z , Franke K , Zuberbier T . Thymic stromal lymphopoietin promotes MRGPRX2-Triggered degranulation of skin mast cells in a STAT5-Dependent manner with further support from JNK. Cells. 2021; 10 (1): 102.

[68] Lan F , Li J , Miao W . GZMK-expressing CD8(+) T cells promote recurrent airway inflammatory diseases. Nature. 2025; 638 (8050): 490- 498.

[69] Rochman Y , Leonard WJ . The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis. J Immunol. 2008; 181 (11): 7699- 7705.

[70] Akamatsu T , Watanabe N , Kido M . Human TSLP directly enhances expansion of CD8+ T cells. Clin Exp Immunol. 2008; 154 (1): 98- 106.

[71] Kasuya T , Tanaka S , Tamura J . Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake. Sci Rep. 2023; 13 (1): 1653.

[72] Leichner TM , Satake A , Harrison VS . Skin-derived TSLP systemically expands regulatory T cells. J Autoimmun. 2017; 79: 39- 52.

[73] Tanaka Y , Yokoyama Y , Kambayashi T . Skin-derived TSLP stimulates skin migratory dendritic cells to promote the expansion of regulatory T cells. Eur J Immunol. 2023; 53 (10): e2350390.

[74] Adhikary PP , Tan Z , Page BDG , Hedtrich S . TSLP as druggable target - a silver-lining for atopic diseases? Pharmacol Ther. 2021; 217: 107648.

[75] Parnes JR , Molfino NA , Colice G , Martin U , Corren J , Menzies-Gow A . Targeting TSLP in asthma. J Asthma Allergy. 2022; 15: 749- 765.

[76] Adhikary PP , Idowu T , Tan Z . Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases. EMBO Mol Med. 2024; 16 (7): 1630- 1656.

[77] Wang J , Zhou Y , Zhang H . Pathogenesis of allergic diseases and implications for therapeutic interventions. Signal Transduct Targeted Ther. 2023; 8 (1): 138.

[78] Bao Y , Zhu X . Role of chemokines and inflammatory cells in respiratory allergy. J Asthma Allergy. 2022; 15: 1805- 1822.

[79] Matera MG , Rogliani P , Calzetta L , Cazzola M . TSLP inhibitors for asthma: current status and future prospects. Drugs. 2020; 80 (5): 449- 458.

[80] Yan S , Yang B , Qin H , Du C , Liu H , Jin T . Exploring the therapeutic potential of monoclonal antibodies targeting TSLP and IgE in asthma management. Inflamm Res. 2024; 73 (9): 1425- 1434.

[81] Zhuang W , Li Z . Antibody targeting TSLP suppresses DSS-induced colitis and activation of the JAK2/STAT5 pathway in mice. Eur Cytokine Netw. 2023; 34 (4): 46- 53.

[82] Wang X , Kong Y , Qiu T , et al. Development of a novel humanized anti-TSLP monoclonal antibody, QX008N, and exploration of combination therapy of anti-TSLP antibody and anti-IL-4R antibody. Int Immunopharmacol. 2024; 142 (Pt A): 113102.

[83] Shi Z , Jiang W , Wang M , et al. Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis. Mol Cell Biochem. 2017; 430 (1-2): 161- 169.

[84] 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 (5): e316.

[85] Akenroye A , Boyce JA , Kita H . Targeting alarmins in asthma: from bench to clinic. J Allergy Clin Immunol. 2025; 155 (4): 1133- 1148.

[86] Hoy SM . Tezepelumab: first approval. Drugs. 2022; 82 (4): 461- 468.

[87] Nagase H , Suzukawa M , Oishi K , Matsunaga K . Biologics for severe asthma: the real-world evidence, effectiveness of switching, and prediction factors for the efficacy. Allergol Int. 2023; 72 (1): 11- 23.

[88] Corren J , Menzies-Gow A , Chupp G . Efficacy of tezepelumab in severe, uncontrolled asthma: pooled analysis of the PATHWAY and NAVIGATOR clinical trials. Am J Respir Crit Care Med. 2023; 208 (1): 13- 24.

[89] Menzies-Gow A , Colice G , Griffiths JM . NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020; 21 (1): 266.

[90] Miralles-López JC , Antolín-Amérigo D , García-Moguel I , Domínguez-Ortega J , Delgado-Romero J , Quirce S . Positioning of tezepelumab in severe asthma. J Investig Allergol Clin Immunol. 2024; 34 (1): 1- 11.

[91] Gauvreau GM , O'Byrne PM , Boulet LP . Effects of an antiTSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014; 370 (22): 2102- 2110.

[92] Corren J , Parnes JR , Wang L . Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017; 377 (10): 936- 946.

[93] Corren J , Pham TH , Garcia Gil E . Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy. 2022; 77 (6): 1786- 1796.

[94] Pham TH , Chen C , Colice G , Parnes JR , Griffiths JM , Cook B . Tezepelumab normalizes serum interleukin-5 and -13 levels in patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2021; 127 (6): 689- 691.

[95] Menzies-Gow A , Corren J , Bourdin A . Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021; 384 (19): 1800- 1809.

[96] Corren J , Larson D , Altman MC . Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: a randomized controlled trial. J Allergy Clin Immunol. 2023; 151 (1): 192- 201.

[97] De Corso E , Hellings PW , Fokkens WJ . Thymic stromal lymphopoietin (TSLP):evidence in respiratory epithelial-driven diseases including chronic rhinosinusitis with nasal polyps. Curr Allergy Asthma Rep. 2024; 25 (1): 7.

[98] Chiang S , Lee SE . New concepts in barrier dysfunction in CRSwNP and emerging roles of tezepelumab and dupilumab. Am J Rhinol Allergy. 2023; 37 (2): 193- 197.

[99] Shen S , Xian M , Yan B , Lan F , Wang C , Zhang L . Anti-thymic stromal lymphopoietin monoclonal antibody in patients with chronic rhinosinusitis with nasal polyps (DUBHE):rationale and design of a multicenter, randomized, double-blind, placebo-controlled study. Asia Pac Allergy. 2024; 14 (1): 26- 31.

[100] Fei Y , Li N , Qian W . A phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of SHR-1905, a long-acting anti-thymic stromal lymphopoietin antibody, in healthy subjects. Front Pharmacol. 2024; 15: 1400696.

[101] Rogliani P , Manzetti GM , Bettin FR , D'Auria M , Calzetta L . Investigational thymic stromal lymphopoietin inhibitors for the treatment of asthma: a systematic review. Expet Opin Invest Drugs. 2024; 33 (1): 39- 49.

[102] Deiteren A , Bontinck L , Conickx G . A first-in-human, single and multiple dose study of lunsekimig, a novel anti-TSLP/anti-IL-13 NANOBODY® compound, in healthy volunteers. Clin Transl Sci. 2024; 17 (6): e13864.

[103] O'Byrne PM , Panettieri RA, Jr. , Taube C , Brindicci C , Fleming M , Altman P . Development of an inhaled anti-TSLP therapy for asthma. Pulm Pharmacol Ther. 2023; 78: 102184.

[104] Laitano R , Calzetta L , Cavalli F , Cazzola M , Rogliani P . Delivering monoclonal antibodies via inhalation: a systematic review of clinical trials in asthma and COPD. Expet Opin Drug Deliv. 2023; 20 (8): 1041- 1054.

[105] Calzetta L , Aiello M , Frizzelli A . Investigational treatments in phase I and II clinical trials: a systematic review in asthma. Biomedicines. 2022; 10 (9): 2330.

[106] Kim SH , Kim Y . Tailored biologics selection in severe asthma. Tuberc Respir Dis. 2024; 87 (1): 12- 21.

[107] Roy P , Rafa ZI , Haque SN . The impact of tezepelumab in uncontrolled severe asthma: a systematic review of randomized controlled trials. Cureus. 2022; 14 (12): e32156.

[108] Roufosse F . Targeting the interleukin-5 pathway for treatment of eosinophilic conditions other than asthma. Front Med. 2018; 5: 49.

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