Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation

Hiroki Kabata,Steven F Ziegler,Tanel Mahlakõiv,Anne-Laure Flamar,Saya Moriyama,David Artis,Hans-Reimer Rodewald

doi:10.1038/s41385-020-0266-x

Abstract

Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.

Highlights

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine produced by epithelial cells, keratinocytes, fibroblasts, and stromal cells in the context of infection and inflammation.[1]
TSLP plays a vital role in papain-induced innate immune-mediated type 2 airway inflammation Papain is a proteolytic enzyme that is used in food industries and is known to cause occupational asthma.[27,28]
TSLP directly stimulates CD4 + T cells, but not ILC2s, to induce adaptive immune-mediated type 2 airway inflammation Since our data suggested that TSLP directly stimulates ILC2s to promote papain-induced innate immune-mediated type 2 airway inflammation (Fig. 3), we evaluated whether TSLP directly affects lymphoid cells during adaptive immune-mediated type 2 airway inflammation

Summary

Introduction

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine produced by epithelial cells, keratinocytes, fibroblasts, and stromal cells in the context of infection and inflammation.[1] Numerous studies have implicated TSLP in allergic diseases, including genome-wide association studies, which found that single nucleotide polymorphisms in TSLP locus were associated with an increased risk of asthma and atopic dermatitis.[2,3,4,5] the expression level of TSLP in the airway of asthmatic patients and the skin of atopic dermatitis patients was highly increased.[6,7,8] In agreement with these studies, a lack of TSLP signaling resulted in reduced Th2 cell-mediated inflammation in murine models of airway inflammation and atopic dermatitis.[9,10,11,12] Based on these findings, an anti-human TSLP antibody (Tezepelumab, AMG 157) was developed and showed significant suppressive effects on airway inflammation and bronchoconstriction in patients with asthma.[13,14] TSLP is increasingly being recognized as a critical cytokine inducing type 2 inflammation and a therapeutic target in the treatment of allergic diseases

Methods

Results

Conclusion