HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling

Zhixuan Loh, Jennifer Simpson, Ashik Ullah, Vivian Zhang, Wan J Gan, Jason P Lynch, Rhiannon B Werder, Al Amin Sikder, Katie Lane, Choon Boon Sim, Enzo Porrello, Stuart B Mazzone, Peter D Sly, Raymond J Steptoe, Kirsten M Spann, Maria B Sukkar, John W Upham and Simon Phipps

PLOS Pathogens, 2020, vol. 16, issue 7, 1-21

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.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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1008651

DOI: 10.1371/journal.ppat.1008651

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