Open AccessHMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling
Author(s) -
Zhixuan Loh,
Jennifer Simpson,
Ashik Ullah,
Vivian Zhang,
Wan Jun Gan,
Jason P. Lynch,
Rhian B. Werder,
Al Amin Sikder,
Katie Lane,
Choon Boon Sim,
Enzo R. Porrello,
Stuart B. Mazzone,
Peter D. Sly,
Raymond J. Steptoe,
Kirsten Spann,
Maria B. Sukkar,
John W. Upham,
Simon Phipps
Publication year - 2020
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1008651
Subject(s) - hmgb1 , inflammation , innate lymphoid cell , rage (emotion) , immunology , biology , asthma , innate immune system , microbiology and biotechnology , medicine , cancer research , immune system , neuroscience
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.