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Identification of a novel HIF-1α-αMβ2 integrin-NETosis axis in fibrotic interstitial lung disease

Khawaja, AA; Chong, DLW; Sahota, J; Mikolasch, TA; Pericleous, C; Ripoll, VM; Booth, HL; Khan, S; Rodriguez-Justo, M; Giles, IP; et al. Khawaja, AA; Chong, DLW; Sahota, J; Mikolasch, TA; Pericleous, C; Ripoll, VM; Booth, HL; Khan, S; Rodriguez-Justo, M; Giles, IP; Porter, JC (2020) Identification of a novel HIF-1α-αMβ2 integrin-NETosis axis in fibrotic interstitial lung disease. Frontiers in Immunology, 11. p. 2190. ISSN 1664-3224 https://doi.org/10.3389/fimmu.2020.02190
SGUL Authors: Chong, Deborah Lia Wah

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Abstract

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold, <0.05), and trans-endothelial migration (+1.9-fold, p < 0.05). Hypoxia also increased neutrophil expression of the αM (+3.1-fold, p < 0.001) and αX (+1.6-fold, p < 0.01) integrin subunits. Interestingly, NET formation was induced by αMβ2 integrin activation and prevented by cation chelation. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. In conclusion, HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β2 integrins. Our results identify a novel HIF-1α- αMβ2 integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD.

Item Type: Article
Additional Information: Copyright © 2020 Khawaja, Chong, Sahota, Mikolasch, Pericleous, Ripoll, Booth, Khan, Rodriguez-Justo, Giles and Porter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Frontiers in Immunology
ISSN: 1664-3224
Dates:
DateEvent
15 October 2020Published
11 August 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
M136Rosetrees Trusthttp://dx.doi.org/10.13039/501100000833
MR/K004158/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
URI: https://openaccess.sgul.ac.uk/id/eprint/112329
Publisher's version: https://doi.org/10.3389/fimmu.2020.02190

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