Thymic Stromal Lymphopoietin (TSLP) is a protein that functions as a signaling molecule, or cytokine, within the immune system. It is produced by epithelial cells that form the lining of the body’s barrier surfaces, including the skin, lungs, and gastrointestinal tract. These cells release TSLP in response to various triggers, such as mechanical injury, chemical irritants, or the presence of infectious microbes. Once released, TSLP acts as an initial alarm that begins a cascade of immune activities, recruiting other cells to the site of the disturbance.
The Primary Function of TSLP
When epithelial cells at barrier surfaces detect damage or threats, they release TSLP as a first-line defense. As an “alarmin” cytokine, it signals tissue damage to the immune system, initiating a protective Type 2 inflammatory response geared toward eliminating parasites and allergens. Upon release, TSLP activates dendritic cells, which act as messengers carrying information about the threat to nearby lymph nodes.
In the lymph nodes, these activated dendritic cells present the information to T cells, influencing them to become T helper 2 (Th2) cells. These Th2 cells combat allergens and parasitic infections by producing their own cytokines, which recruit other cells like eosinophils and mast cells to amplify the inflammation. TSLP also directly influences innate lymphoid cells type 2 (ILC2s), which are rapid responders that produce large quantities of Type 2 cytokines.
TSLP’s Role in Allergic and Inflammatory Diseases
While protective, the TSLP mechanism can become detrimental when overactivated. In individuals with certain allergic conditions, excessive or dysregulated TSLP production leads to chronic inflammation. This overproduction turns the body’s alarm system into a source of persistent irritation, contributing to the symptoms of several diseases characterized by a Type 2 inflammatory response.
In severe asthma, for instance, inhaled allergens, viruses, or pollutants trigger airway epithelial cells to release high levels of TSLP. This initiates an inflammatory cascade in the lungs, leading to the recruitment of eosinophils and other immune cells. The resulting inflammation causes airway constriction, increased mucus production, and bronchial hypersensitivity. The continuous presence of TSLP helps sustain this inflammation, making airways prone to severe symptoms.
A similar process occurs in atopic dermatitis (eczema), where a compromised skin barrier allows allergens to penetrate the skin, prompting skin cells to produce TSLP. This leads to chronic skin inflammation, intense itching, and further breakdown of the skin barrier. In chronic rhinosinusitis with nasal polyps, elevated TSLP in the nasal passages contributes to severe inflammation, tissue swelling, and the formation of polyps.
Therapeutic Targeting of TSLP
Given its role in driving Type 2 inflammation, TSLP has become a focus for therapeutic intervention in allergic diseases. The strategy involves blocking the TSLP protein before it can deliver its activating signal to other immune cells. This is achieved with monoclonal antibodies, which are laboratory-produced molecules engineered to bind to a specific target like the TSLP cytokine.
One such medication, tezepelumab, is a human monoclonal antibody designed to target TSLP. It works by binding directly to the TSLP protein, effectively neutralizing it. This action prevents TSLP from attaching to its receptor on immune cells like dendritic cells and innate lymphoid cells, interrupting the inflammatory cascade at its source.
This intervention stops the activation of downstream immune cells responsible for the symptoms of diseases like severe asthma. The result is a reduction in airway inflammation, a decrease in exacerbations, and improved lung function. This therapeutic approach is approved for individuals with severe asthma not well-controlled by other medications, and it can be effective regardless of the specific triggers of their inflammation.
Emerging Research on TSLP
Scientific understanding of TSLP is expanding beyond its role in allergic diseases. Researchers are investigating its involvement in other biological processes, revealing a more complex function for this cytokine. Studies suggest TSLP’s influence extends to gut health, tissue repair, and the development of cancer.
In the gastrointestinal tract, TSLP appears to contribute to maintaining a balanced environment, or homeostasis. It helps regulate the immune response to the community of microbes in the gut, playing a part in both tolerance and defense. In the context of tissue repair, TSLP may aid in healing processes at barrier surfaces following injury.
The role of TSLP in cancer is complex and appears to be dual-natured. In some types of cancer, such as breast and pancreatic cancer, TSLP can promote an inflammatory environment that supports tumor growth. In other contexts, it may be involved in anti-tumor immune responses, highlighting that TSLP is a versatile signaling molecule.