TSLP: A Key Target in Allergic and Inflammatory Diseases

1. Production and Mechanism of Action of TSLP

TSLP is produced by airway epithelial cells upon exposure to environmental factors such as allergens and viruses. TSLP binds to and activates the TSLP receptor (a heterodimer composed of TSLPR and IL-7Rα chains) expressed on dendritic cells, leading to the activation of signal transduction and transcription activator (STAT), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), and downstream signaling factors. These pathways participate in inducing the expression of genes involved in cell activation, resulting in various types of airway inflammation and contributing to its chronicity and severity (Figure 1) ^[1].

Structure of TSLP

TSLP exists in two isoforms: long-form TSLP (lfTSLP) and short-form TSLP (sfTSLP). lfTSLP is predominantly expressed under inflammatory conditions and exhibits pro-inflammatory functions, while sfTSLP is constitutively expressed and possesses antimicrobial and immunoregulatory properties. The C-terminal region of TSLP contains a 34-amino acid peptide segment (MKK34) with significant antimicrobial activity, capable of disrupting bacterial membrane structures.

Functions of TSLP

Immune Activation: TSLP promotes Th2-type immune responses by activating dendritic cells, mast cells, and T cells.

Antimicrobial Activity: Both sfTSLP and lfTSLP demonstrate potent antimicrobial effects, particularly in defending the skin and mucosal barriers ^[2].

Metabolic Regulation: TSLP improves obesity and metabolic disorders by inducing excessive sebum secretion, leading to white adipose tissue loss.

2. Research on TSLP-Related Diseases

TSLP plays a critical role in various diseases, including:

● Asthma and Allergic Diseases: TSLP is a key driver of asthma and allergic inflammation. It promotes the release of IL-4, IL-5, and IL-13 by activating Th2-type immune responses, leading to airway inflammation and remodeling ^[6][7]. Anti-TSLP monoclonal antibodies, such as tezepelumab, have demonstrated significant efficacy in severe asthma and CRSwNP ^[3][4].

● Metabolic Diseases: TSLP improves obesity, glucose metabolism, and non-alcoholic fatty liver disease by inducing excessive sebum secretion and white adipose tissue loss.

● Dermatological Diseases: TSLP plays a significant role in atopic dermatitis, psoriasis, and alopecia. It promotes skin inflammation and pruritus by activating mast cells and dendritic cells . Additionally, TSLP promotes hair follicle stem cell proliferation and hair regeneration after skin injury ^[5].

● Esophageal Diseases: TSLP promotes Th2-type inflammatory responses in eosinophilic esophagitis (EoE) and reflux esophagitis (RE). TSLP-neutralizing antibodies significantly alleviate esophageal inflammation and pathological damage.

● Systemic Sclerosis and Interstitial Lung Disease: TSLP levels are significantly elevated in the sera of patients with systemic sclerosis (SSc) and correlate with the severity of skin fibrosis and interstitial lung disease (ILD).

● Cancer and Immunotherapy: TSLP affects the efficacy of immunotherapy by regulating immune cell function in the tumor microenvironment. Inhibiting TSLP may be a potential strategy to enhance the efficacy of immunotherapy (Figure 2) ^[6].

3. Development Progress in TSLP-Targeted Therapies

Current therapeutic strategies against TSLP include:

● Monoclonal Antibodies: Tezepelumab is the first approved anti-TSLP monoclonal antibody for severe asthma, demonstrating good efficacy and safety.

● Peptide Inhibitors: High-affinity cyclic peptide inhibitors have been developed through structural design and disulfide bond stabilization to competitively block the binding of TSLP to its receptor.

● Small Molecule Compounds: Virtual screening and molecular dynamics simulations have identified certain natural compounds with strong binding affinity to TSLP, which can be used to develop novel drugs.

● Inhalation Therapy: For instance, ecleralimab, which reduces systemic side effects and improves therapeutic efficiency through local administration.

4. CUSABIO's TSLP-related Products

Thymic Stromal Lymphopoietin (TSLP), as a pleiotropic cytokine, plays a crucial role in immune regulation, inflammatory responses, and metabolic homeostasis. It regulates immune and inflammatory responses as well as metabolic homeostasis through signaling pathways such as JAK/STAT, MAPK, and PI3K/AKT. Its dysfunction is closely associated with Th2-type diseases such as asthma and atopic dermatitis. In recent years, monoclonal antibodies against TSLP, such as tezepelumab, have demonstrated significant efficacy in clinical trials, highlighting the therapeutic potential of this target. To facilitate in-depth understanding of TSLP's molecular mechanisms and drug development, highly specific and active recombinant proteins and antibody tools are essential. CUSABIO offers a variety of TSLP recombinant proteins, antibodies, and ELISA-related products to support receptor-binding experiments, cellular functional studies, and antibody drug screening, thereby accelerating TSLP-related translational medical research.

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