Thymic Stromal Lymphopoietin: To Cut a Long Story Short

Abstract

Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

Keywords: Atopic Diseases; DC, dendritic cell; Gut Homeostasis; IFN, interferon; IL, interleukin; ILC, innate lymphoid cells; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; TLR, toll-like receptor; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin; TSLPR, thymic stromal lymphopoietin protein receptor; Therapeutic Targets; Thymic Stromal Lymphopoietin; Treg, regulatory T cells.

Figure 1

The human TSLP gene locus. Different transcription factors bind to different promoter regions, inducing expression of long or short TSLP, depending on the context, tissue, and stimulus. RXR, retinoic X receptor; VDR, vitamin D receptor.

Figure 2

Induction of TSLP expression by endothelial cells and DC conditioning. In microbe-inhabited barrier surfaces, commensal bacteria such as E coli and nutrients such as vitamin D enhance short TSLP expression. Pathogens such as S typhimurium and allergens such as house dust mite upregulate the long isoform.