Abstract

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 growth in 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	Loh, Zhixuan; Simpson, Jennifer; Ullah, Ashik; Zhang, Vivian; Gan, Wan J; Lynch, Jason P; Werder, Rhiannon B; Sikder, Al Amin; Lane, Katie; Sim, Choon Boon; Porrello, Enzo; Mazzone, Stuart B; Sly, Peter D; Steptoe, Raymond J; Spann, Kirsten M; Sukkar, Maria B; Upham, John W; Phipps, Simon
Journal	PLOS PATHOGENS
Pages	e1008651
Volume	16
Date	1/07/2020
Grant ID	ID1023756
Funding Body	NHMRC
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1371/journal.ppat.1008651
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