RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

Jaisy Arikkatt,Wan Jun Gan,Manuel Ar Ferreira,Stuart B Mazzone,John W Upham,Maria B Sukkar,Kirsten M Spann,Rhiannon B Werder,Zhixuan Loh,Md Ashik Ullah,Vivan Zhang,Simon Phipps,Peter D Sly,Kirsty Renfree Short,Jennifer Simpson

doi:10.7554/elife.21199

Abstract

Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.

Highlights

Asthma is a chronic inflammatory disease of the airways that affects more than 300 million people worldwide (Pawankar, 2014)
To understand the role of receptor for advanced glycation endproducts (RAGE) in an early life respiratory viral infection, seven-day old RAGE-deficient (RAGE-) and wild-type (WT) mice were inoculated with pneumonia virus of mice (PVM) and viral infection was assessed by Quantitative polymerase chain reaction (qPCR) at seven days post-infection
RAGE deficient mice displayed a significantly higher percentage of PVM infected airway epithelial cells (AECs) in the respiratory tract compared to WT mice at seven dpi (Figure 1B & C)

Summary

Introduction

Asthma is a chronic inflammatory disease of the airways that affects more than 300 million people worldwide (Pawankar, 2014). The resulting increase in viral load in the airway epithelium led to the release of HMGB1, which via the activation of TLR4 was instrumental in driving ASM remodelling during an early life viral infection, as well as the development of mucus hypersecretion and airway hyperreactivity in later life. These features occurred independently of type-2 inflammation and granulocytic inflammation, suggesting that blocking HMGB1 may be a promising therapeutic approach to prevent the development of airway remodelling, which can occur in the absence of eosinophilic or neutrophilic inflammation

Results

Discussion

Materials and methods

AG-20B-0033B-C100

Funding Funder