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; Simon Phipps

doi:10.1371/journal.ppat.1008651

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

PLoS Pathog. 2020 Jul 13;16(7):e1008651. doi: 10.1371/journal.ppat.1008651. eCollection 2020 Jul.

Authors

Zhixuan Loh^{1

2}, Jennifer Simpson^{1

3}, Ashik Ullah^{1

3}, Vivian Zhang³, Wan J Gan¹, Jason P Lynch^{1

3}, Rhiannon B Werder^{1

3}, Al Amin Sikder^{1

3}, Katie Lane¹, Choon Boon Sim⁴, Enzo Porrello⁴, Stuart B Mazzone^{1

5}, Peter D Sly^{6

7}, Raymond J Steptoe⁸, Kirsten M Spann⁹, Maria B Sukkar¹⁰, John W Upham⁸, Simon Phipps^{1

3

7}

Affiliations

¹ School of Biomedical Sciences, The University of Queensland, Queensland, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
³ QIMR Berghofer Medical Research Institute, Queensland, Australia.
⁴ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia.
⁵ Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia.
⁶ Children's Health and Environment Program, Child Health Research Centre, University of Queensland, Queensland, Australia.
⁷ Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, Australia.
⁸ UQ Diamantina Institute, The University of Queensland, Queensland, Australia.
⁹ School of Biomedical Sciences, Queensland University of Technology, Queensland, Australia.
¹⁰ Graduate School of Health, Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Airway Remodeling / immunology*
Animals
HMGB1 Protein / immunology*
Inflammation / immunology*
Lymphocytes / immunology*
Mice
Muscle, Smooth / immunology*
Muscle, Smooth / pathology
Receptor for Advanced Glycation End Products / immunology

Substances

HMGB1 Protein
HMGB1 protein, mouse
Receptor for Advanced Glycation End Products

Grants and funding

This work was supported by an NHMRC project grant (S.P. and J.W.U.; ID1023756), an equipment grant from the Rebecca L. Cooper Medical Research Foundation (S.P.), an Australian Infectious Disease Research Excellence Award (S.P.), and an Australian Research Council Future Fellowship (S.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.