Thymic Stromal Lymphopoietin in Asthma Pathophysiology

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that functions as a frontline alarmin, released upon environmental insults such as allergens, viruses or pollutants. Binding to a heterodimeric receptor comprising the TSLP receptor chain (TSLPR) and the interleukin-7 receptor α-chain (IL-7Rα), TSLP orchestrates a cascade of type 2 immune responses. It activates dendritic cells to prime Th2 differentiation, stimulates group 2 innate lymphoid cells (ILC2s) to produce IL-5 and IL-13, and can directly engage eosinophils and other effector cells. These events drive airway inflammation, hyperresponsiveness and remodelling that characterise asthma. Genetic polymorphisms in the TSLP locus associate with asthma susceptibility, emphasising its clinical relevance. Therapeutic blockade of TSLP with a monoclonal antibody has shown broad efficacy across eosinophilic and non-eosinophilic phenotypes, reducing exacerbations, improving lung function and enabling corticosteroid reduction. Beyond its pro-inflammatory long isoform, TSLP also exists in a short homeostatic form, highlighting nuanced immunoregulatory roles. Investigation of cell-specific receptor requirements has revealed context-dependent mechanisms, underscoring TSLP’s centrality and versatility in asthma pathogenesis and therapy.

Research from Nature Portfolio

Recent structural studies have elucidated the ternary assembly of TSLP with TSLPR and IL-7Rα, revealing how allosteric receptor engagement leverages cytokine flexibility and electrostatics to potentiate signalling. These insights have guided the design of neutralising antibodies that exploit conformational heterogeneity to achieve high-potency antagonism. Complementary work has dissected the opposing functions of TSLP isoforms in the airway epithelium: the long form disrupts barrier integrity and promotes inflammation, whereas the short form preserves epithelial junctions and may confer protection, suggesting novel avenues for isoform-selective interventions.

Thymic Stromal Lymphopoietin in Asthma Pathophysiology publication trend

The graph below shows the total number of articles in thymic stromal lymphopoietin in asthma pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Thymic Stromal Lymphopoietin (TSLP): An epithelial-derived alarmin cytokine that initiates type 2 immune responses through receptor engagement. TSLP Receptor (TSLPR): The cytokine-specific α subunit that pairs with IL-7Rα to form the functional TSLP receptor. IL-7 Receptor α-chain (IL-7Rα): The shared subunit that completes the TSLP receptor complex and mediates downstream signalling. Group 2 Innate Lymphoid Cells (ILC2s): Innate effector cells that respond to epithelial alarmins by secreting type 2 cytokines. Type 2 Inflammation: An immune polarisation characterised by IL-4, IL-5 and IL-13 production, driving eosinophilia and allergic pathology. Tezepelumab: A human monoclonal antibody that binds TSLP and prevents its interaction with the receptor complex, inhibiting type 2 signalling.

References

1. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nature Communications (2017).
2. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Frontiers in Immunology (2018).
3. Distinct roles of short and long thymic stromal lymphopoietin isoforms in house dust mite-induced asthmatic airway epithelial barrier disruption. Scientific Reports (2016).
4. 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. Respiratory Research (2020).
5. SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respiratory Research (2020).
6. Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation. Mucosal Immunology (2020).