Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

Tara E. Sutherland; Dominik Rückerl; Nicola Logan; Sheelagh Duncan; Thomas A. Wynn; Judith E. Allen

doi:10.1371/journal.ppat.1007423

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

Tara E. Sutherland^* (Corresponding Author), Dominik Rückerl, Nicola Logan, Sheelagh Duncan, Thomas A. Wynn, Judith E. Allen^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

Abstract

Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

Original language	English
Article number	: e1007423
Number of pages	27
Journal	PLoS Pathogens
Volume	14
Issue number	11
DOIs	https://doi.org/10.1371/journal.ppat.1007423
Publication status	Published - 30 Nov 2018

Bibliographical note

Acknowledgments

The authors gratefully thank Stella Pearson, Brian Chan and Yvonne Harcus for excellent technical assistance, as well as Professor Rick M Maizels for the kind provision of Nippostrongylus brasiliensis and Dr. Martin Waterfall and Dr. Gareth Howell for flow cytometry support. The authors also thank Biological Services Facility staff at the University of Edinburgh and the University of Manchester, for help with animal husbandry. TES acknowledges the support of the Manchester Collaborative Centre for Inflammation Research, a joint venture between The University of Manchester and GlaxoSmithKline.

This work was supported by: Medical Research Council UK, http://www.mrc.ac.uk/, grant numbers MR/K01207X/1 and MR/J001929/1 and
Wellcome Trust, http://wellcome.ac.uk, grant number 106898/A/15/Z to JEA; Medical Research Foundation UK joint funding with Asthma UK, https://www.medicalresearchfoundation.org.uk
and https://www.asthma.org.uk, grant number MRFAUK-2015-302 to TES. The funders had no role in study design, data collection and analysis,
decision to publish or preparation of the manuscript.

Data Availability Statement

All relevant data are within the paper and its Supporting Information files

Keywords

Animals
Intercellular Signaling Peptides and Proteins/metabolism
Lectins/metabolism
Lung/immunology
Mice
Inbred BALB C
Inbred C57BL
Knockout
Nematode Infections/immunology
Nippostrongylus/immunology
Receptors
Cell Surface/deficiency
Signal Transduction
Strongylida Infections/immunology
beta-N-Acetylhexosaminidases/metabolism

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Sutherland_PP_Ym1_induces_REMa_VoR
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Cite this

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title = "Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection",

abstract = "Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.",

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author = "Sutherland, {Tara E.} and Dominik R{\"u}ckerl and Nicola Logan and Sheelagh Duncan and Wynn, {Thomas A.} and Allen, {Judith E.}",

note = "Acknowledgments The authors gratefully thank Stella Pearson, Brian Chan and Yvonne Harcus for excellent technical assistance, as well as Professor Rick M Maizels for the kind provision of Nippostrongylus brasiliensis and Dr. Martin Waterfall and Dr. Gareth Howell for flow cytometry support. The authors also thank Biological Services Facility staff at the University of Edinburgh and the University of Manchester, for help with animal husbandry. TES acknowledges the support of the Manchester Collaborative Centre for Inflammation Research, a joint venture between The University of Manchester and GlaxoSmithKline. This work was supported by: Medical Research Council UK, http://www.mrc.ac.uk/, grant numbers MR/K01207X/1 and MR/J001929/1 and Wellcome Trust, http://wellcome.ac.uk, grant number 106898/A/15/Z to JEA; Medical Research Foundation UK joint funding with Asthma UK, https://www.medicalresearchfoundation.org.uk and https://www.asthma.org.uk, grant number MRFAUK-2015-302 to TES. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. ",

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T1 - Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

AU - Sutherland, Tara E.

AU - Rückerl, Dominik

AU - Logan, Nicola

AU - Duncan, Sheelagh

AU - Wynn, Thomas A.

AU - Allen, Judith E.

N1 - Acknowledgments The authors gratefully thank Stella Pearson, Brian Chan and Yvonne Harcus for excellent technical assistance, as well as Professor Rick M Maizels for the kind provision of Nippostrongylus brasiliensis and Dr. Martin Waterfall and Dr. Gareth Howell for flow cytometry support. The authors also thank Biological Services Facility staff at the University of Edinburgh and the University of Manchester, for help with animal husbandry. TES acknowledges the support of the Manchester Collaborative Centre for Inflammation Research, a joint venture between The University of Manchester and GlaxoSmithKline. This work was supported by: Medical Research Council UK, http://www.mrc.ac.uk/, grant numbers MR/K01207X/1 and MR/J001929/1 and Wellcome Trust, http://wellcome.ac.uk, grant number 106898/A/15/Z to JEA; Medical Research Foundation UK joint funding with Asthma UK, https://www.medicalresearchfoundation.org.uk and https://www.asthma.org.uk, grant number MRFAUK-2015-302 to TES. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2018/11/30

Y1 - 2018/11/30

N2 - Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

AB - Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

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KW - Lung/immunology

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KW - Knockout

KW - Nematode Infections/immunology

KW - Nippostrongylus/immunology

KW - Receptors

KW - Cell Surface/deficiency

KW - Signal Transduction

KW - Strongylida Infections/immunology

KW - beta-N-Acetylhexosaminidases/metabolism

U2 - 10.1371/journal.ppat.1007423

DO - 10.1371/journal.ppat.1007423

M3 - Article

SN - 1553-7374

VL - 14

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 11

M1 - : e1007423

ER -

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

Abstract

Bibliographical note

Data Availability Statement

Keywords

Access to Document

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