IL4RA signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses in vivo

Harris, Alison J. and Mirchandani, Ananda S. and Lynch, Ruairi W. and Murphy, Fiona and Delaney, Liam and Small, Donna and Coelho, Patricia and Watts, Emily R. and Sadiku, Pranvera and Griffith, David and Dickinson, Rebecca S. and Clark, Eilidh and Willson, Joseph A. and Morrison, Tyler and Mazzone, Massimilliano and Carmeliet, Peter and Ghesquiere, Bart and O'Kane, Cecilia and McAuley, Danny and Jenkins, Steve J. and Whyte, Moira K.B. and Walmsley, Sarah R. (2019) IL4RA signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses in vivo. American Journal of Respiratory and Critical Care Medicine, 200 (2). pp. 235-246. ISSN 1535-4970 (https://doi.org/10.1164/rccm.201808-1599OC)

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Abstract

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.  Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.  Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1a-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.  Conclusions: We describe an important interaction whereby IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.

  • Item type:Article
    ID code:86381
    Dates:
    Date
    Event
    8 March 2019
    Published
    8 March 2019
    Accepted
    29 August 2018
    Submitted
    Notes:Funding Information: Supported by a Wellcome Trust Senior Clinical Fellowship award (098516 and 209220, S.R.W.) and a postdoctoral fellowship award (110086, A.S.M.). Publisher Copyright: Copyright © 2019 by the American Thoracic Society Harris, Mirchandani, Lynch, et al.: IL-4 Limits Neutrophilic Responses to Hypoxia, Am J Respir Crit Care Med Vol 200, Iss 2, pp 235–246, DOI: 10.1164/rccm.201808-1599OC
    Subjects:Medicine
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:03 Aug 2023 12:17
    Last modified:29 Apr 2024 00:59
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/86381
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