Local blockade of TSLP receptor alleviated allergic disease by regulating airway dendritic cells

Abstract

Thymic stromal lymphopoietin (TSLP) emerges as a central mediator of T helper cell (Th)2-dominant allergic diseases. However, the role of TSLP receptor (TSLPR) in allergen-induced Th2 priming, and the effects of TSLP signaling blocking on the development of asthma remain unclear. Here we showed that allergen challenge caused a rapid accumulation of TSLP in the airways of asthmatic mice, correlating well with eosinophils counts and interleukin (IL)-5 productions. When TSLP signaling was blocked by intratracheal administration of anti-TSLPR antibody before sensitization, eosinophilic airway inflammation, goblet cell hyperplasia and Th2 cytokines productions were significantly reduced. The alleviating effects of TSLPR blocking were achieved by inhibition of maturation and migration of airway dendritic cells (DCs), as well as their abilities of initiating CD4+T cell responses. Thus, local application of anti-TSLPR prevented Th2-mediated airway inflammation, at least partly, by regulating DCs function, which might be exploited to develop novel treatments for asthma.

Introduction

The participation of genetic, environmental factors and immune regulation complicate the pathogenesis of allergic asthma, a chronic respiratory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). However, a dysregulated Th2 polarization and expansion has been presumed to play critical roles in the development of the disease, and mechanisms underlying the Th2 differentiation in allergen-induced airway responses are presently under intensive investigation [1], [2].

Strategically positioned at high antigen-exposed sites, airway DCs have been regarded as critical initiators of allergic inflammation, not only by their abilities of processing and presenting inhaled antigenic information to the draining pulmonary lymph nodes (LNs), but also by their capabilities of activating naïve T cells, and even determining the type of immune response in the afflicted areas [3], [4]. It is recognized that the abilities of DCs to direct different Th responses largely depend on the signals DCs receive from both the invading antigens as well as the tissue microenvironments factors [5], [6]. Compelling data about toll-like receptors (TLRs) on DCs have illuminated the mechanisms by which microbe-molecules drive DC-mediated Th1 differentiation. However, which factors and how these factors condition DCs to induce Th2 differentiation are relatively less known to date. Delineating the signaling through which DCs prime T cells to differentiate into Th2 effector cells is central to understand the pathogenesis of allergic asthma and develop efficient treatment for the disease.

Thymic stromal lymphopoietin (TSLP) emerges as one of the most powerful mediators to induce DC-mediated Th2 response [7], [8]. It endows DCs with the ability to stimulate naïve T cells and promote Th2 differentiation by triggering the production of proallergic cytokines (IL-4, IL-5, IL-13). Also, TSLP activates CD11c⁺ DCs to produce chemokines CCL17 and CCL22, recruiting Th2 cells to the draining LNs. Specific expression of TSLP in atopic dermatitis lesions and asthmatic airway, and the induction of pronounced airway inflammation in the Tslp transgene mice implicated this novel cytokine in allergic diseases [9], [10], [11]. Further evidence to support the importance of TSLP signaling in allergic airway inflammation was derived from TSLP receptor (TSLPR)-deficient (Tslpr−/−) mice which exhibited remarkably decreased airway inflammation and goblet cell hyperplasia upon ovalbumin (OVA) challenge in comparison to wide type [12].

TSLPR is a novel type 1 cytokine receptor, which, combined with IL-7 receptor-α (IL-7Rα), constitutes TSLP receptor complex [13]. TSLPR possesses a tyrosine residue near its carboxyl terminus, which can associate with phosphorylated Stat5 and mediate multiple biological functions when engaged with TSLP [14]. The above studies illuminated the significance of TSLP/TSLPR in allergic diseases, and suggest a new therapeutic target for the treatment of allergic diseases, but the data from tslp overexpression or Tslpr−/− mice couldn't exclude the systematic effects which have been evidenced by previous studies to be associated with some immunological disorders [15], [16], [17]. Moreover, previous studies demonstrated that intrapulmonary antagonizing of functional molecules on effector cells was effective in abrogating the cardinal features of asthma, while intraperitoneal regulating of circulating leukocytes only partially inhibited airway responses [18], [19], [20]. Here we adopted local administration of anti-TSLPR antibody in allergen-primed asthmatic mice to assess the effects of TSLPR blocking in the development of airway inflammation, and sought to identify the involved mechanism, with more attentions placed on DCs, which is believed to be critical in Th2-dominated allergic disease.