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.

Keywords: asthma; atopic dermatitis; cancer; inflammation; thymic stromal lymphopoietin.

Figure 1

Schematic representation of the production of thymic stromal lymphopoietin (TSLP) and its signaling complex via a cooperative stepwise mechanism on the surface of cellular targets. A plethora of triggers including allergens, cigarette smoke extracts, cytokines, viral, bacterial and fungal products, and tryptase can activate lung and gut epithelial cells and keratinocytes to release TSLP. The latter, which is positively charged, binds to thymic stromal lymphopoietin receptor (TSLPR), which is negatively charged, with high affinity and fast kinetics. Then, IL-7Rα associates with performed TSLPR:TSLP binary complex to form the ternary TSLPR-TSLP-IL-7Rα complex (44). This receptor complex on cells co-expressing TSLPR and IL-7Rα phosphorylates JAK and STAT5 to initiate proinflammatory signaling.

Figure 2

Schematic representation of cellular targets of thymic stromal lymphopoietin (TSLP). Several triggers can activate lung and gut epithelial cells and keratinocytes to release TSLP. This cytokine can also be produced by activated mast cells (, –57) and dendritic cells (DCs) (26, 58). Tryptase, released by mast cell activates the protease-activated receptor 2 receptor on fibroblasts (53, 59) and keratinocytes (53) to release TSLP. TSLP activates DCs (37, 44, 60), ILC2 (–63), CD4⁺ T and Th2 cells (64, 65), NKT cells (66), CD8⁺ T cells (67) and B cells (68, 69), Treg (35, 70), eosinophils (71, 72), neutrophils (73), murine (74), but not human basophils (9), monocytes (75), mast cells (, –78), macrophages (79), platelets (80, 81), and sensory neurons (53).

Figure 3

Thymic stromal lymphopoietin (TSLP) produced mainly by gut and epithelial cells and keratinocytes but also by dendritic cells, mast cells, and fibroblasts initiates signaling by establishing a ternary complex with thymic stromal lymphopoietin receptor (TSLPR) and IL-7Rα. Tezepelumab, a human mAb anti-TSLP, binds with high affinity to TSLP and blocks the formation of TSLPR:TSLP: IL-7Rα ternary complex on effector cells. In particular, the variable heavy chain of tezepelumab binds to TSLP, while the variable light chain fragment does not interact with TSLP (44). Tezepelumab inhibits in vitro human DC maturation and chemokine production induced by TSLP (44) and reduced exacerbations and improved quality of life in patients with severe uncontrolled asthma (124).