HMGB1 amplifies ILC2 cytokine production and mediates ILC2-induced airway smooth muscle remodelling during severe viral bronchiolitis and subsequent asthma — ASN Events
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  2. Workshop 4: Mucosal Immunity
  3. HMGB1 amplifies ILC2 cytokine production and mediates ILC2-induced airway smooth muscle remodelling during severe viral bronchiolitis and subsequent asthma

HMGB1 amplifies ILC2 cytokine production and mediates ILC2-induced airway smooth muscle remodelling during severe viral bronchiolitis and subsequent asthma (#39)

Md Ashik Ullah 1 2 , Zhixuan Loh 2 , Jennifer Simpson 1 2 , Vivian Zhang 1 2 , Jason P Lynch 1 2 , Rhiannon Werder 1 2 , Peter D Sly 3 , Kirsten Spann 3 4 , Maria Sukkar 5 , John W Upham 6 , Simon Phipps 1 2
  1. QIMR Berghofer Medical Research Institute, Herston, Queensland , Australia
  2. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland , Australia
  3. Queensland Children’s Medical Research Institute, University of Queensland, Brisbane, Queensland , Australia
  4. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland , Australia
  5. School of Pharmacy, University of Technology Sydney, Sydney, New South Wales, Australia
  6. Lung and Allergy Research Centre, University of Queensland, Brisbane, Queensland , Australia

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses can cause aberrant tissue remodelling, as observed in the asthmatic airway. Respiratory viral infections contribute to asthma onset and exacerbations by causing tissue damage, alarmin release, and type 2 innate lymphoid cell (ILC2) expansion. However, whether alarmin-activated ILC2s mediate airway smooth muscle (ASM) remodelling remains unknown. Here we simulated a gene-environment interaction through pneumoviral infection of neonatal interferon regulatory factor (IRF)–7 deficient mice, and identified that ASM growth commenced in early-life, and was dependent on the alarmins high-mobility group box 1 (HMGB1) and IL-33. HMGB1 was released by the injured airway epithelium, ASM cells, and ILC2s, which localised adjacent to and within the ASM layer. In a series of in-vitro experiments using murine ILC2s cultured alone or together with murine ASM cells, we found that IL-33  induced the release of HMGB1 from ILC2s. HMGB1 in turn induced IL-5, IL-9, IL-13 and amphiregulin production by ILC2s in a receptor for advanced glycation end products (RAGE)-dependent manner. Intriguingly, autocrine IL-13 amplified its own production via HMGB1/RAGE axis. IL-13 also induced ASM cell release of HMGB1, which induced ASM proliferation via TLR4 and not RAGE. Importantly, neutralisation of HMGB1 in early-life ameliorated viral bronchiolitis and prevented subsequent asthma. Hence, therapeutic targeting of HMGB1 may act as a novel preventative in early-life by dampening type-2 inflammation as well as attenuating virus-associated ASM remodelling.

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