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Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma.

ABSTRACT: Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that has emerged as a critical player in the development and progression of allergy and asthma. It is primarily produced by epithelial cells and functions as a potent immune system activator. TSLP acts through interaction with its receptor complex, composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha chain (IL-7Rα), activating downstream complex signalling pathways. The TSLP major isoform, known as long-form TSLP (lfTSLP), is upregulated in the airway epithelium of patients with allergic diseases. More research is warranted to explore the precise mechanisms by which short-form TSLP (sfTSLP) regulates immune responses. Understanding the dynamic interplay between TSLP and the dysfunctional epithelium provides insights into the mechanisms underlying allergy and asthma pathogenesis. Targeting TSLP represents an important therapeutic strategy, as it may upstream disrupt the inflammatory cascade and alleviate symptoms associated with allergic inflammation.

SUBMITTER: Smolinska S

PROVIDER: S-EPMC10454039 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma.

Smolinska Sylwia S Antolín-Amérigo Darío D Popescu Florin-Dan FD Jutel Marek M

International journal of molecular sciences 20230812 16

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that has emerged as a critical player in the development and progression of allergy and asthma. It is primarily produced by epithelial cells and functions as a potent immune system activator. TSLP acts through interaction with its receptor complex, composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha chain (IL-7Rα), activating downstream complex signalling pathways. The TSLP major isoform, known as long-form TSLP (lf ...[more]

PMID: 37628907

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Project description:RationaleSevere asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.ObjectivesTo assess whether BT affects gene signatures in bronchial epithelial cells (BECs).MethodsIn this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.Measurements and main resultsTranscriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.ConclusionsThese data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.

Project description:Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

Dataset Information

Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma.

Publications

Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma.

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