A thymic stromal lymphopoietin polymorphism may provide protection from asthma by altering gene expression

Abstract

Background Genome‐wide association studies have identified associations of the single nucleotide polymorphism rs1837253 in the thymic stromal lymphopoietin (TSLP) gene with asthma, allergic disease and eosinophilia. The TSLP gene encodes two isoforms, long and short, and previous studies have indicated functional differences between these two isoforms. Objective We investigated the expression of these TSLP isoforms in response to a pro‐inflammatory signal, and the role of the rs1837253 genotype in gene isoform regulation. Methods We cultured nasal epithelial cells of asthmatic and non‐asthmatic subjects and evaluated poly(I:C)‐induced TSLP protein secretion using multiplex protein assays and gene expression profiles of the TSLP isoforms, and related genes using real‐time qPCR. We correlated these profiles with rs1837253 genotype. Results Asthmatic nasal epithelial cells exhibited increased TSLP protein secretion compared with nasal epithelial cells from healthy controls. The long TSLP isoform was more responsive to poly(I:C) stimulation. Additionally, the minor T allele of rs1837253 was less inducible than the major C allele, suggesting differential regulation; this may explain the “protective” effects of the T allele in asthma. Conclusion Our results provide important insights into the differential regulation and function of TSLP isoforms, including the role of TSLP rs1837253 polymorphisms in allergic inflammatory processes. Clinical relevance The key finding on the influence of TSLP genetic variation on disease expression/endotype could provide basis for investigation into targeted biologics for anti‐TSLP therapies.

Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma

“…The role of TSLP in asthma is underscored by genome-wide association studies that have identified associations between asthma risk and single-nucleotide polymorphisms (SNPs) in the TSLP gene [38][39][40]. These include rs1837253 [41,42], which has been shown to regulate TSLP production in nasal epithelial cells [43] and influence asthma manifestation [44]. TSLP has also been implicated in aspirin-exacerbated respiratory disease (AERD), which is characterized by asthma, chronic rhinosinusitis with nasal polyps, and intolerance of cyclooxygenase-1 inhibitors.…”

Human Lung-Resident Macrophages Express and Are Targets of Thymic Stromal Lymphopoietin in the Tumor Microenvironment

“…Differences between IL-4 and IL-13 have been reported on the mouse macrophages responsiveness to TSLP [98]. Whatever the interpretation of these results, given the relevance of TSLP [99][100][101][102][103][104] and T H 2 cytokines in the pathogenesis of asthma [105,106], it is likely that these observations have translational relevance contributing to clinical manifestations of chronic inflammatory lung disorders.…”

Developments in the field of allergy in 2020 through the eyes of Clinical and Experimental Allergy

“…We have finally entered the much‐anticipated era of personalized medicine for asthma, and several articles evaluated biologics and the variation in individual response to these in people with asthma 25‐27 , 28‐36 , 37 , 38 Others evaluated more traditional treatments for asthma, such as corticosteroids or mechanisms that may underlie impaired airway function in asthma 39‐59 . New interventions studied in clinical trials included air cleaners, triple inhaler therapy, an oral prostaglandin D2 antagonist 60‐62 and other more preliminary data from various interventions, from cinnamon and bacterial peptides to allergen immunotherapy 63‐67 .…”