sly-hmgb1amplifiesilc2-2020.pdf (2.79 MB)
HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling
journal contribution
posted on 2020-07-01, 00:00 authored by Z Loh, J Simpson, A Ullah, V Zhang, W J Gan, J P Lynch, R B Werder, A A Sikder, K Lane, C B Sim, E Porrello, S B Mazzone, Peter Sly, R J Steptoe, K M Spann, M B Sukkar, J W Upham, S PhippsType-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 illdefined. 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.