Thymic stromal lymphopoietin, TSLP, is a protein within the human body. This cytokine plays a role in various physiological and pathological processes, primarily within the immune system. TSLP was initially discovered as a growth factor from mouse thymic stromal cells, supporting B lymphocyte survival and proliferation. It helps regulate immune responses, acting as a signaling molecule that influences different immune cells.
TSLP is classified as an interleukin (IL)-2-like cytokine and alarmin, sharing a common ancestor with IL-7. The human TSLP gene is located on chromosome 5q22.1, adjacent to a cluster of genes associated with atopic conditions on 5q31. It is a relatively small protein, consisting of 132 amino acids and weighing around 15 kDa, with a substantial impact on immune function.
TSLP’s Role in Immune Regulation
TSLP is primarily produced by epithelial cells, which form the protective linings of various organs. These cells are found in the skin, lungs, gut, and tonsils, acting as the body’s first line of defense against external threats. Stromal cells and mast cells also contribute to TSLP production.
In its normal function, TSLP acts as an “alarm bell” for the immune system. When epithelial barriers encounter potential threats, such as allergens or microbes, TSLP is released. This release signals to various immune cells, including dendritic cells, mast cells, basophils, and T cells, directing them to initiate appropriate responses. TSLP specifically influences the polarization of dendritic cells, guiding them to promote a type 2 immune response.
TSLP binds to a specific receptor complex on immune cells, consisting of the IL-7 receptor alpha chain (IL-7Rα) and the TSLP receptor chain (TSLPR). This binding triggers intracellular signaling pathways, including the activation and phosphorylation of STAT5, which then influences gene expression. This mechanism helps fine-tune immune reactions, allowing the body to respond effectively to environmental challenges and maintain immune balance.
TSLP’s Connection to Allergic Diseases
TSLP plays a role in the development and progression of common allergic conditions. Its overactivity contributes to the inflammatory processes observed in these diseases. In asthma, TSLP from the airway epithelium promotes the activation of immune cells that drive airway inflammation, leading to symptoms like wheezing and shortness of breath.
This cytokine can induce dendritic cells to prime naive T cells, resulting in the production of pro-allergic cytokines such as Interleukin-4 (IL-4), Interleukin-5 (IL-5), and Interleukin-13 (IL-13), while reducing Interleukin-10 (IL-10) and Interferon-gamma (IFN-γ). These shifts in cytokine profiles contribute to the characteristic type 2 inflammation seen in allergic asthma.
In atopic dermatitis, also known as eczema, TSLP produced by skin cells contributes to chronic inflammation and skin barrier dysfunction. TSLP-activated Langerhans cells in the epidermis can induce the production of pro-inflammatory cytokines, such as TNF-alpha, by T cells, potentially leading to atopic dermatitis. Elevated TSLP levels in the skin of individuals with eczema contribute to the persistent itching, redness, and dryness.
TSLP is also implicated in food allergies, where it can promote immune responses that lead to allergic reactions upon exposure to certain food proteins. It can directly activate innate immune cells, including mast cells and basophils, to produce pro-inflammatory and type 2 cytokines, which can initiate or worsen allergic inflammation even in the absence of T lymphocytes and IgE antibodies. Understanding TSLP’s role in these diseases has made it a target for new therapeutic strategies.
TSLP’s Influence Beyond Allergies
While TSLP is associated with allergic diseases, its influence extends to other inflammatory conditions and certain types of cancer. Research indicates TSLP can be involved in inflammatory bowel disease (IBD), a group of chronic inflammatory conditions affecting the digestive tract. In the gut, TSLP produced by intestinal epithelial cells may help maintain tolerance to commensal flora by modulating dendritic cell function. However, TSLP dysregulation could contribute to uncontrolled inflammation in IBD.
TSLP has also been implicated in various types of cancer, though its role can be complex and context-dependent. It may promote tumor growth in some cancers by fostering an immune suppressive environment or by directly stimulating cancer cell proliferation. In other instances, it might have a tumor-suppressing effect by activating anti-tumor immune responses. These roles are actively being investigated, with ongoing studies exploring the precise mechanisms by which TSLP influences tumor biology.
TSLP’s involvement is also being explored in conditions such as chronic obstructive pulmonary disease (COPD) and certain forms of arthritis. In COPD, TSLP may contribute to airway inflammation and remodeling, similar to its role in asthma. TSLP’s diverse functions highlight its broad impact on immune regulation and disease pathogenesis.
Developing Therapies Targeting TSLP
Understanding TSLP’s role in various inflammatory and allergic diseases has led to new therapeutic strategies aimed at blocking its activity. The concept is to neutralize TSLP, preventing it from binding to its receptor and initiating the inflammatory cascade. By inhibiting TSLP, these treatments aim to reduce inflammation and alleviate symptoms in affected individuals.
One example of a TSLP-targeted therapy is Tezepelumab, a monoclonal antibody approved for severe asthma. Tezepelumab works by binding directly to TSLP, preventing it from interacting with its receptor on immune cells. This blockade reduces the activation of immune cells involved in type 2 inflammation, leading to decreased inflammatory markers and improved lung function. Clinical trials have demonstrated its effectiveness in reducing asthma exacerbations and improving quality of life.
Other therapies targeting TSLP are in various stages of development for conditions including atopic dermatitis and chronic rhinosinusitis with nasal polyps. These investigational treatments often use similar mechanisms, employing antibodies to intercept TSLP before it can exert its pro-inflammatory effects. TSLP-targeted therapies highlight the understanding of specific molecular pathways in disease and the potential for precision medicine in treating complex immune-mediated conditions.