Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer

Abstract

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.

A thymic stromal lymphopoietin polymorphism may provide protection from asthma by altering gene expression

“…The high fold change of lfTSLP is likely due to its very low expression levels at steady state, while the short form is expressed constitutively in much higher abundance. Our results further highlight a potentially important functional dichotomy between the two TSLP isoforms …”

“…The rs1837253 T allele (minor allele) is associated with a lower risk of asthma and hence considered to have a “protective” effect on asthma development . The TSLP gene encodes two transcript variants in humans: a long TSLP isoform (lfTSLP) and a short TSLP isoform (sfTSLP) . The C terminal of the long isoform, common to both isoforms, can be used to evaluate total TSLP transcripts.…”

Cutaneous expression of thymic stromal lymphopoietin (TSLP) in vitiligo patients: a case‐control study

“…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 …”

“…These emerging observations greatly widen the role of TSLP in different human diseases. 18 The goal of this study was to provide new insights into the relationship between vitiligo and TSLP mRNA expression level which is possibly involved in vitiligo pathogenesis. Our results revealed that there was a statistically significant difference of TSLP mRNA expression levels with lower expression in vitiligo patients than in control subjects (P < 0.001).…”

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019

“…Upon activation, mast cells store and release a large repertoire of biologically active mediators that have potential positive or negative effects on various target cells [25, 26]. These cells and their mediators have been canonically associated with a detrimental role in allergic diseases [4, 27].…”