The Proinflammatory Role of Epithelial TSLP in Severe Asthma

Article

The complexity and heterogeneity of asthma reflects its wide range of potential triggers, clinical manifestations, and underlying drivers. Various disease pathways – spanning both innate and adaptive immunity – can serve as tributaries to the chronic inflammatory state at the core of the disease.1,2

In many individuals with severe, uncontrolled asthma, pathogenic processes can overlap dynamically in ways that can change over time.3 This can makes it difficult to base clinical management decisions the apparent predominance of a specific inflammatory pathway and its constituent mediators.3-5 As a result, the estimated 1 million people in the U.S. contending with severe, uncontrolled asthma face ongoing challenges that can evolve into exacerbations, hospitalizations and consequent use of health care resources.6,8

In recent years, new insights into the role of the airway epithelium in asthma have provided a framework for understanding how diverse and changeable inflammatory signals can converge to promote severe clinical disease. The significance of airway epithelium in asthma derives not only from the well-known structural damage it undergoes but from the proinflammatory signals it initiates.4,9

As the first point of contact between potential asthma triggers and the lungs, the epithelium sits at the headwaters of multiple distinct inflammatory cascades. Whether the immediate trigger is a pathogen, allergen, or irritant, the epithelium can respond by releasing proinflammatory cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP).9 First identified as a growth factor in the early 1990s, TSLP has more recently attracted considerable scientific interest because of its capacity to drive multiple downstream innate and adaptive immune responses.10

TSLP Action Across Major Inflammatory Categories

Despite its vast phenotypic diversity, asthma can be categorized at a high level based on major patterns of inflammation. About two-thirds of individuals with severe asthma exhibit type 2 (T2) inflammatory patterns.11 T2 inflammation includes classic allergy, where antigen presentation to type 2 helper T (Th2) cells promotes the production of allergen-specific IgE antibodies, mast cell degranulation, and release of proinflammatory mediators.9

T2 inflammation also encompasses nonallergic pathways that share key features with allergic inflammation. In lieu of antigen presentation and clonal selection of IgE-producing B cells, type 2 innate lymphoid cells (ILC2s) directly provide cytokine signals promoting recruitment and activation of eosinophils.9

While a significant proportion of patients with severe asthma exhibit T2 inflammation, there remains a substantial portion of patients with severe asthma who exhibit a non-T2 inflammatory pattern, where target-tissue inflammation is primarily mediated by IL-17A, produced by Th17 cells. Eosinophils do not play a major role in non-T2 inflammation, although neutrophil proliferation may occur. Non-T2 inflammation is commonly associated with late-onset asthma.9

As shown in Figure 1 in the review by Gauvreau and colleagues, each of these broad inflammatory pathways can ladder back to the epithelial release of TSLP. A broad array of innate and adaptive immune cells – including dendritic cells, naïve and differentiated T cells, ILC2 cells, and mast cells – respond to TSLP via TSLP receptors. TSLP thus is capable of activating diverse downstream inflammatory cascades.9

Impact on Airway Structural Changes

Regardless of the underlying inflammatory processes at play, airway narrowing through progressive tissue remodeling poses major challenges to asthma management that increase in urgency with disease severity.12

Early research demonstrates a potential role of TSLP in airway remodeling. Fibroblasts and airway smooth muscle cells (ASMCs) both express TSLP receptors. TSLP has been shown in vitro to stimulate collagen production by fibroblasts and promote ASMC proliferation. ASMCs produce TSLP as well as respond to it; airway remodeling may be mediated in part through TSLP cross-talk between ASMCs and mast cells.9,12

TSLP in Severe Asthma

Multiple lines of evidence suggest a central role of TSLP in the pathogenesis of severe asthma, largely independent of inflammatory phenotype and biomarker patterns:13-17

  • Airway TSLP is overexpressed in patients with asthma and increases with disease severity. Airway TSLP expression has been found to be higher in patients with asthma compared with healthy controls, and the elevated levels correlated significantly with asthma severity.
  • Airway TSLP expression correlates with reduced lung function. A study of 70 patients with asthma of varying severity found that airway TSLP concentrations were inversely correlated with FEV1.
  • TSLP may drive reduced corticosteroid responses. ILC2s obtained by bronchoalveolar lavage from patients with severe asthma showed a reduced in vitro response to dexamethasone after exposure to TSLP. Further, the reduced response to dexamethasone was greater in patients with higher airway TSLP expression.

Conclusion

Our increased understanding of the role of TSLP in asthma underscores the importance of the airway epithelium as the first point of contact with environmental stimuli. TSLP, a key epithelial cytokine produced in response to environmental triggers, can drive multiple downstream inflammatory pathways that may contribute to severe, uncontrolled asthma. Because TSLP sits at the top of these disparate inflammatory cascades, there is evidence that it plays a central role in the pathogenesis of severe asthma.

References

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  14. Liu S, Verma M, Michalec L, et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin. J Allergy Clin Immunol. 2018;141(1):257-268.
  15. Cao L, Liu F, Liu Y, et al. TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast. Exp Lung Res. 2018;44(6):288-301.
  16. Ko HK, Cheng SL, Lin CH, et al. Blood tryptase and thymic stromal lymphopoietin levels predict the risk of exacerbation in severe asthma. Sci Rep. 2021;11(1):8425.
  17. Ying S, O'Connor B, Ratoff J, 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(12):8183-8190.
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