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Identification of a Novel HIF-1α-αMß2 Integrin-NET Axis in Fibrotic Interstitial Lung Disease.
Khawaja, Akif A; Chong, Deborah L W; Sahota, Jagdeep; Mikolasch, Theresia A; Pericleous, Charis; Ripoll, Vera M; Booth, Helen L; Khan, Saif; Rodriguez-Justo, Manuel; Giles, Ian P; Porter, Joanna C.
Afiliação
  • Khawaja AA; Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
  • Chong DLW; Centre for Rheumatology, University College London, London, United Kingdom.
  • Sahota J; Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
  • Mikolasch TA; Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
  • Pericleous C; Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
  • Ripoll VM; Interstitial Lung Disease Service, University College London Hospital NHS Foundation Trust, London, United Kingdom.
  • Booth HL; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  • Khan S; Centre for Rheumatology, University College London, London, United Kingdom.
  • Rodriguez-Justo M; Interstitial Lung Disease Service, University College London Hospital NHS Foundation Trust, London, United Kingdom.
  • Giles IP; Institute of Nuclear Medicine, University College London, London, United Kingdom.
  • Porter JC; Department of Histopathology, University College London Hospital NHS Foundation Trust, London, United Kingdom.
Front Immunol ; 11: 2190, 2020.
Article em En | MEDLINE | ID: mdl-33178179
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 αMß2 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 ß2 integrins. Our results identify a novel HIF-1α- αMß2 integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Pulmonares Intersticiais / Antígenos CD18 / Antígeno CD11b / Subunidade alfa do Fator 1 Induzível por Hipóxia / Armadilhas Extracelulares / Pulmão / Neutrófilos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Front Immunol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Pulmonares Intersticiais / Antígenos CD18 / Antígeno CD11b / Subunidade alfa do Fator 1 Induzível por Hipóxia / Armadilhas Extracelulares / Pulmão / Neutrófilos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Front Immunol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido