IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

Alison J Harris; Ananda S Mirchandani; Ruairi W Lynch; Liam Delaney; Donna Small; Patricia Coelho; Emily R Watts; Pranvera Sadiku; David Griffith; Rebecca S Dickinson; Eilidh Clark; Joseph A Willson; Tyler Morrison; Massimilliano Mazzone; Peter Carmeliet; Bart Ghesquiere; Cecilia O'Kane; Danny McAuley; Steve J Jenkins; Moira K B Whyte; Sarah R Walmsley

doi:10.1164/rccm.201808-1599OC

IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

Alison J Harris, Ananda S Mirchandani, Ruairi W Lynch, Liam Delaney, Donna Small, Patricia Coelho, Emily R Watts, Pranvera Sadiku, David Griffith, Rebecca S Dickinson, Eilidh Clark, Joseph A Willson, Tyler Morrison, Massimilliano Mazzone, Peter Carmeliet, Bart Ghesquiere, Cecilia O'Kane, Danny McAuley, Steve J Jenkins, Moira K B WhyteSarah R Walmsley

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Abstract

RATIONALE: Acute respiratory distress syndrome (ARDS) is defined by the presence of systemic hypoxia and consequent upon disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.

OBJECTIVES: We aimed to test the hypothesis that during acute lung inflammation tissue production of pro-resolution type 2 cytokines (IL-4 and IL-13) dampen the pro-inflammatory effects of hypoxia through suppression of Hypoxia Inducible Factor (HIF-1)α-mediated neutrophil adaptation, resulting in resolution of the lung injury.

METHODS: Neutrophil activation of IL4Ra signaling pathways were explored ex vivo in human ARDS patient samples, in vitro following 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 bronchoalveolar lavage from ARDS patients and its receptor was identified on inflamed lung neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α dependent hypoxic survival and limited pro-inflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent upon 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 IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil mediated acute lung injury. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.

Original language	English
Pages (from-to)	235
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	200
Issue number	2
Early online date	08 Mar 2019
DOIs	https://doi.org/10.1164/rccm.201808-1599OC
Publication status	Early online date - 08 Mar 2019

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10.1164/rccm.201808-1599OCLicence: Unspecified

IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo
© 2019 by the American Thoracic Society. This is an open access Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Accepted author manuscript, 1.53 MBLicence: CC BY-NC

Donna Small
- d.smallqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Senior Lecturer
Person: Academic

Cite this

Harris, A. J., Mirchandani, A. S., Lynch, R. W., Delaney, L., Small, D., Coelho, P., Watts, E. R., Sadiku, P., Griffith, D., Dickinson, R. S., Clark, E., Willson, J. A., Morrison, T., Mazzone, M., Carmeliet, P., Ghesquiere, B., O'Kane, C., McAuley, D., Jenkins, S. J., ... Walmsley, S. R. (2019). IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo. American Journal of Respiratory and Critical Care Medicine, 200(2), 235. Advance online publication. https://doi.org/10.1164/rccm.201808-1599OC

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title = "IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo",

abstract = "RATIONALE: Acute respiratory distress syndrome (ARDS) is defined by the presence of systemic hypoxia and consequent upon disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.OBJECTIVES: We aimed to test the hypothesis that during acute lung inflammation tissue production of pro-resolution type 2 cytokines (IL-4 and IL-13) dampen the pro-inflammatory effects of hypoxia through suppression of Hypoxia Inducible Factor (HIF-1)α-mediated neutrophil adaptation, resulting in resolution of the lung injury.METHODS: Neutrophil activation of IL4Ra signaling pathways were explored ex vivo in human ARDS patient samples, in vitro following 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 bronchoalveolar lavage from ARDS patients and its receptor was identified on inflamed lung neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α dependent hypoxic survival and limited pro-inflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent upon 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 IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil mediated acute lung injury. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.",

author = "Harris, {Alison J} and Mirchandani, {Ananda S} and Lynch, {Ruairi W} and Liam Delaney and Donna Small and Patricia Coelho and Watts, {Emily R} and Pranvera Sadiku and David Griffith and Dickinson, {Rebecca S} and Eilidh Clark and Willson, {Joseph A} and Tyler Morrison and Massimilliano Mazzone and Peter Carmeliet and Bart Ghesquiere and Cecilia O'Kane and Danny McAuley and Jenkins, {Steve J} and Whyte, {Moira K B} and Walmsley, {Sarah R}",

year = "2019",

month = mar,

day = "8",

doi = "10.1164/rccm.201808-1599OC",

language = "English",

volume = "200",

pages = "235",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "2",

}

Harris, AJ, Mirchandani, AS, Lynch, RW, Delaney, L, Small, D, Coelho, P, Watts, ER, Sadiku, P, Griffith, D, Dickinson, RS, Clark, E, Willson, JA, Morrison, T, Mazzone, M, Carmeliet, P, Ghesquiere, B, O'Kane, C , McAuley, D, Jenkins, SJ, Whyte, MKB & Walmsley, SR 2019, 'IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo', American Journal of Respiratory and Critical Care Medicine, vol. 200, no. 2, pp. 235. https://doi.org/10.1164/rccm.201808-1599OC

TY - JOUR

T1 - IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

AU - Harris, Alison J

AU - Mirchandani, Ananda S

AU - Lynch, Ruairi W

AU - Delaney, Liam

AU - Small, Donna

AU - Coelho, Patricia

AU - Watts, Emily R

AU - Sadiku, Pranvera

AU - Griffith, David

AU - Dickinson, Rebecca S

AU - Clark, Eilidh

AU - Willson, Joseph A

AU - Morrison, Tyler

AU - Mazzone, Massimilliano

AU - Carmeliet, Peter

AU - Ghesquiere, Bart

AU - O'Kane, Cecilia

AU - McAuley, Danny

AU - Jenkins, Steve J

AU - Whyte, Moira K B

AU - Walmsley, Sarah R

PY - 2019/3/8

Y1 - 2019/3/8

N2 - RATIONALE: Acute respiratory distress syndrome (ARDS) is defined by the presence of systemic hypoxia and consequent upon disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.OBJECTIVES: We aimed to test the hypothesis that during acute lung inflammation tissue production of pro-resolution type 2 cytokines (IL-4 and IL-13) dampen the pro-inflammatory effects of hypoxia through suppression of Hypoxia Inducible Factor (HIF-1)α-mediated neutrophil adaptation, resulting in resolution of the lung injury.METHODS: Neutrophil activation of IL4Ra signaling pathways were explored ex vivo in human ARDS patient samples, in vitro following 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 bronchoalveolar lavage from ARDS patients and its receptor was identified on inflamed lung neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α dependent hypoxic survival and limited pro-inflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent upon 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 IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil mediated acute lung injury. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.

AB - RATIONALE: Acute respiratory distress syndrome (ARDS) is defined by the presence of systemic hypoxia and consequent upon disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.OBJECTIVES: We aimed to test the hypothesis that during acute lung inflammation tissue production of pro-resolution type 2 cytokines (IL-4 and IL-13) dampen the pro-inflammatory effects of hypoxia through suppression of Hypoxia Inducible Factor (HIF-1)α-mediated neutrophil adaptation, resulting in resolution of the lung injury.METHODS: Neutrophil activation of IL4Ra signaling pathways were explored ex vivo in human ARDS patient samples, in vitro following 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 bronchoalveolar lavage from ARDS patients and its receptor was identified on inflamed lung neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α dependent hypoxic survival and limited pro-inflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent upon 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 IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil mediated acute lung injury. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.

U2 - 10.1164/rccm.201808-1599OC

DO - 10.1164/rccm.201808-1599OC

M3 - Article

C2 - 30849228

SN - 1073-449X

VL - 200

SP - 235

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 2

ER -

IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

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