TSLP Asthma: Inflammatory Pathways in Respiratory Disease

Asthma is a chronic respiratory disease driven by complex immune responses, leading to airway inflammation and obstruction. A key regulator of this process is thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine that initiates and amplifies inflammatory pathways.

Understanding TSLP’s role in asthma pathophysiology offers insight into potential therapeutic targets for both allergic and nonallergic forms of the disease.

TSLP Production In Airway Epithelium

The airway epithelium acts as both a physical barrier and an active participant in immune signaling. TSLP is produced by epithelial cells in response to allergens, pollutants, and viral infections. Primarily secreted by basal and columnar epithelial cells, it plays a role in detecting and responding to external threats. Epithelial damage, whether from mechanical stress or inflammatory mediators, leads to increased TSLP expression, reinforcing its role as an early immune signal.

Environmental triggers such as diesel exhaust, cigarette smoke, and rhinovirus activate intracellular pathways, including NF-κB and STAT transcription factors, driving TSLP expression. Epithelial cells from individuals with asthma exhibit heightened TSLP levels even without acute triggers, suggesting baseline dysregulation that contributes to chronic inflammation. This persistent elevation has been linked to epigenetic modifications and altered regulatory feedback mechanisms.

Mechanical stress from airway constriction further amplifies TSLP secretion, creating a feedback loop that worsens epithelial dysfunction. Studies using bronchial epithelial cell cultures show that cyclic mechanical strain, mimicking bronchoconstriction, increases TSLP release through calcium-dependent signaling pathways, further sensitizing epithelial cells to inflammation.

Receptor Interactions On Immune Cells

TSLP exerts its effects by binding to a heterodimeric receptor complex composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha (IL-7Rα). This receptor pairing is expressed on dendritic cells, mast cells, eosinophils, and T helper lymphocytes, enabling TSLP to drive inflammatory signaling. Binding to its receptor complex triggers intracellular pathways, primarily via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, leading to inflammatory mediator production.

Dendritic cells, which express high levels of TSLPR and IL-7Rα, are among the first to respond. Upon activation, they upregulate OX40 ligand (OX40L), promoting T helper 2 (Th2) cell differentiation. This skews the immune response toward a Th2-dominant profile, increasing interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) production. These cytokines promote eosinophil recruitment, mucus hypersecretion, and airway hyperresponsiveness. Dendritic cells from individuals with asthma show heightened sensitivity to TSLP, leading to exaggerated Th2 polarization and inflammation.

Mast cells also respond to TSLP, with direct signaling enhancing their survival and activation. TSLP engagement increases degranulation and the release of histamine, tryptase, and prostaglandins, contributing to bronchoconstriction and airway remodeling. Additionally, TSLP stimulates mast cell production of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), further amplifying local inflammation. Increased mast cell density in lung tissue has been linked to TSLP presence in the airway microenvironment.

Eosinophils, another key inflammatory cell type, do not express TSLPR at baseline but are indirectly activated through TSLP-stimulated dendritic cells and Th2 cytokines. TSLP promotes eosinophil recruitment by upregulating eotaxins, chemokines that guide eosinophil migration. Once in airway tissue, eosinophils release toxic granules, exacerbating epithelial damage and perpetuating inflammation.

TSLP In Allergic Asthma

TSLP is a key driver of allergic asthma, modulating airway inflammation in response to allergens such as pollen, dust mites, and mold spores. Individuals with allergic asthma exhibit heightened sensitivity to these triggers, leading to exaggerated inflammatory responses. Elevated TSLP levels in bronchial epithelial cells correlate with disease severity and exacerbation frequency.

Beyond acute inflammation, TSLP contributes to airway remodeling, a process involving subepithelial fibrosis, goblet cell hyperplasia, and increased smooth muscle mass. These structural changes lead to irreversible airflow limitation and reduced treatment responsiveness. TSLP directly enhances fibroblast proliferation and extracellular matrix deposition, reinforcing airway remodeling.

Targeting TSLP has emerged as a promising strategy for managing allergic asthma, particularly in patients unresponsive to conventional therapies. Monoclonal antibodies like tezepelumab, which inhibit TSLP activity, have shown efficacy in reducing exacerbations and improving lung function. Blocking TSLP lowers eosinophil counts and decreases corticosteroid dependence, offering a novel approach for severe allergic asthma.

TSLP In Nonallergic Inflammation

Nonallergic asthma arises from irritants such as air pollution, infections, and occupational exposures, triggering inflammation without allergen-specific IgE involvement. TSLP plays a central role by responding to epithelial stress and amplifying inflammatory pathways. Elevated TSLP levels are particularly noted in neutrophilic airway inflammation, a subtype associated with steroid resistance and poor disease control.

Environmental pollutants such as diesel exhaust, ozone, and cigarette smoke upregulate TSLP in bronchial epithelial cells, leading to persistent airway irritation and remodeling. Unlike allergen-driven responses that primarily activate type 2 inflammation, pollutants induce a broader cytokine release, including interleukin-8 (IL-8) and granulocyte colony-stimulating factor (G-CSF), promoting neutrophil recruitment. This shift toward neutrophilic infiltration is especially relevant in severe asthma cases where corticosteroids are less effective, highlighting the need for alternative treatment strategies targeting TSLP.

Cross Talk With Other Cytokines

TSLP’s role in asthma is part of a broader network of cytokine interactions that shape disease progression. It functions as an upstream regulator, modulating interleukins, chemokines, and growth factors that sustain airway inflammation.

One key interaction involves interleukin-33 (IL-33), another epithelial-derived cytokine implicated in asthma. Both TSLP and IL-33 are released in response to epithelial injury and work together to amplify type 2 inflammation. IL-33 activates group 2 innate lymphoid cells (ILC2s), leading to IL-5 and IL-13 production, which drive eosinophilic inflammation. TSLP enhances this process by increasing IL-33 receptor expression on ILC2s, making them more responsive. This synergy sustains cytokine production, promoting airway hyperresponsiveness and mucus secretion.

TSLP also interacts with interleukin-25 (IL-25), another alarmin involved in asthma. IL-25 promotes Th2 cell and ILC2 expansion, increasing type 2 cytokine secretion. TSLP enhances IL-25-induced inflammation by upregulating its receptor expression on immune cells. This interaction is particularly relevant in severe asthma, where TSLP and IL-25 remain elevated despite corticosteroid therapy. Some experimental biologic treatments aim to inhibit multiple alarmins simultaneously for broader disease control.

TSLP In Comorbid Respiratory Conditions

Beyond asthma, TSLP is implicated in other respiratory diseases characterized by chronic inflammation and epithelial dysfunction, including chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis (CRS), and eosinophilic bronchitis. Elevated TSLP expression in these conditions suggests a broader role in airway disease.

In COPD, TSLP expression is linked to cigarette smoke and pollutants, which induce epithelial damage and inflammation. Unlike asthma, COPD is often dominated by neutrophilic infiltration. TSLP promotes this response by enhancing IL-8 production, a key neutrophil recruiter. Additionally, TSLP contributes to corticosteroid resistance by altering glucocorticoid receptor signaling, making inflammation harder to control with standard therapies. Targeting TSLP could benefit COPD patients with persistent airway inflammation despite treatment.

Chronic rhinosinusitis, particularly the eosinophilic subtype, shares inflammatory features with asthma, including increased TSLP expression in nasal epithelial cells. In CRS with nasal polyps, TSLP drives eosinophilic infiltration and mucus overproduction, mirroring its effects in asthma. This has led to investigations into TSLP-targeting therapies for patients with both asthma and CRS, aiming to alleviate upper and lower airway inflammation simultaneously. Similarly, eosinophilic bronchitis, a condition marked by chronic cough and sputum eosinophilia without airway remodeling, exhibits increased TSLP activity, reinforcing its role in persistent eosinophilic inflammation.