Thymic Stromal Lymphopoietin in Cutaneous Immune-Mediated Diseases

Abstract

Thymic stromal lymphopoietin (TSLP) was initially demonstrated to be critical in regulating inflammatory responses among various allergic disorders (such as atopic dermatitis, food allergy, and asthma). Although two isoforms (short form and long form) of TSLP have been demonstrated in human tissues, the long form of TSLP (lfTSLP) is strongly implicated in the pathogenesis of allergies and cutaneous immune-mediated diseases. The immunomodulatory activity of lfTSLP varies widely, driving T helper (Th) cells polarizing Th2 and Th17 immune responses and inducing itch. Moreover, lfTSLP is closely associated with skin fibrosis, epidermal hyperplasia, angiogenesis, and homeostatic tolerogenic regulations. This review highlights significant progress from experimental and clinical studies on lfTSLP in cutaneous immune-mediated diseases (atopic dermatitis, psoriasis, bullous pemphigoid, systemic sclerosis, chronic spontaneous urticaria, Behçet’s disease, vitiligo, rosacea, systemic lupus erythematosus, and alopecia areata). We also offer original insights into the pleiotropic properties of the cytokine TSLP in various pathophysiological conditions, with significant clinical implications of TSLP-targeted therapies for immune-mediated skin diseases in the future.

The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review

“…Eosinophils, which are central to the pathogenesis of allergic and non-allergic asthma [ 54 , 55 ], express high levels of surface IL-5Rα chain [ 56 ], as well as TSLPR [ 57 ], the IL-4Rα chain common to IL-4R and IL-13R [ 58 , 59 ], and the high-affinity receptor FcεRI [ 60 ]. In addition, further inflammatory cells, including dendritic cells, lung epithelial cells, lymphocytes, mast cells, monocytes, stromal cells, and type 2 innate lymphoid cells have been shown to express the heterodimers IL-4Rα/IL-13Rα1 [ 61 , 62 ] and TSLPR [ 63 , 64 , 65 ], while basophils and mast cells represent the two main cell populations expressing IL-5R and FcεRI [ 66 , 67 ].…”

Monoclonal Antibodies in Treating Chronic Spontaneous Urticaria: New Drugs for an Old Disease

“…TSLP, IL-25, and IL-33 are released following different triggers on epithelia. They start the Th2 inflammatory response, mediating T-cell polarization in Th2 cells [ 112 , 113 , 114 ].…”

“…TSLP, IL-25, and IL-33, the so called “alarmins” probably represent one of the most intriguing targets because they are located upstream of the inflammatory cascade. Hence, blocking the alarmins pathway could potentially be more efficacious and modify the disease course [ 114 ]. Barzolvolimab, suppressing mast cells, could represent another disease-modifying drug [ 115 ].…”

Alarmin Cytokines as Central Regulators of Cutaneous Immunity

“…TSLPR is broadly expressed by immune cells and sensory neurons in the skin. In particular, DCs are important TSLP-responsive immune cell populations ( 27 , 53 – 55 , 82 ). Several DC subsets, including epidermal LCs and dermal type 1 and 2 conventional DCs, respond to keratinocytes-derived TSLP signals to initiate cutaneous adaptive immunity and provide multiple soluble and surface-bound signals that help to guide T cell differentiation, in particular Th2 cells ( 83 – 86 ).…”

“…Alarmins are endogenous molecules that function as danger signals and are rapidly released to the extracellular milieu in response to tissue damage to trigger defensive immune responses ( 26 ). Among them, the proper functions of type 2 alarmin cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, as central orchestrators of T helper 2 (Th2) immunity, are paramount to the skin homeostasis and their dysregulation is commonly associated with chronic allergic inflammation ( 27 – 29 ).…”