Journal
PLOS PATHOGENS
Volume 16, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1008651
Keywords
-
Categories
Funding
- NHMRC [ID1023756]
- Rebecca L. Cooper Medical Research Foundation
- Australian Infectious Disease Research Excellence Award
- Australian Research Council Future Fellowship
Ask authors/readers for more resources
Author summary Asthma can start at any time in life, although most often begins in early childhood. Wheezy viral bronchiolitis is a major independent risk factor for subsequent asthma. However, key knowledge gaps exist in relation to the sequelae of severe viral bronchiolitis and the pathogenic processes that promote type-2 inflammation and airway wall remodelling, cardinal features of asthma. Our study addresses this gap by identifying high-mobility group box 1 as a pathogenic cytokine that contributes to group 2 innate lymphoid cell-induced airway smooth muscle growth. Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growthin vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available