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Soluble ADAM33 augments the pulmonary innate immune response promoting susceptibility to allergic airway inflammation

Soluble ADAM33 augments the pulmonary innate immune response promoting susceptibility to allergic airway inflammation
Soluble ADAM33 augments the pulmonary innate immune response promoting susceptibility to allergic airway inflammation
A disintegrin and metalloproteinase 33 (ADAM33) is an asthma susceptibility gene. A soluble, catalytically active form (sADAM33) has been identified in bronchoalveolar lavage fluid, levels of which correlate with disease severity. To model the role of sADAM33 in asthma, a transgenic mouse, expressing human sADAM33 was generated. sADAM33 mice were found to be more susceptible than controls to allergic airways disease. This led to the hypothesis that induction of sADAM33 expression changes the underlying immune microenvironment in the airway, promoting susceptiblity to allergic airways disease.

To study this, RNA samples from whole lungs of sADAM33 mice and control mice were sequenced for differential expression analysis. Gene ontology identified predominantly immune-related biological processes associated with sADAM33 expression. Validation across a wider cohort of samples using RTqPCR confirmed the up-regulation of lymphocyte effector cell markers (Nkp46, Gzmb), as well as negative regulators of effector responses (Ido1, Pd-l1). Protein levels of GZMB measured by ELISA were significantly increased in sADAM33 mice. Analysis of lymphocyte populations by flow cytometry identified an increased population of CD3-, NKp46+, KLRG1+ positive lymphocytes, which may represent an altered phenotype of innate lymphocyte populations in the airway.

The biology of innate lymphocytes is complex, but there is increasing support for their involvement in allergic disease. The altered phenotype of this cell population within the sADAM33 mice may play an important role in their increased susceptibility to allergic airways disease and warrants further investigation.
ADAM33, innate immune response, allergic asthma, airway inflammation
119 PA1103
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Xu, Yan
c9c742b1-4b1c-4720-956b-12928519e4d0
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Xu, Yan
c9c742b1-4b1c-4720-956b-12928519e4d0
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe

Kelly, Joanne, Freda Carmichael, Davies, Elizabeth R, Xu, Yan, Whitsett, Jeffrey A., Davies, Donna E and Haitchi, Hans Michael (2018) Soluble ADAM33 augments the pulmonary innate immune response promoting susceptibility to allergic airway inflammation. European Respiratory Society (ERS) International Congress 2018, , Paris, France. 15 - 19 Sep 2018. 119 PA1103 .

Record type: Conference or Workshop Item (Poster)

Abstract

A disintegrin and metalloproteinase 33 (ADAM33) is an asthma susceptibility gene. A soluble, catalytically active form (sADAM33) has been identified in bronchoalveolar lavage fluid, levels of which correlate with disease severity. To model the role of sADAM33 in asthma, a transgenic mouse, expressing human sADAM33 was generated. sADAM33 mice were found to be more susceptible than controls to allergic airways disease. This led to the hypothesis that induction of sADAM33 expression changes the underlying immune microenvironment in the airway, promoting susceptiblity to allergic airways disease.

To study this, RNA samples from whole lungs of sADAM33 mice and control mice were sequenced for differential expression analysis. Gene ontology identified predominantly immune-related biological processes associated with sADAM33 expression. Validation across a wider cohort of samples using RTqPCR confirmed the up-regulation of lymphocyte effector cell markers (Nkp46, Gzmb), as well as negative regulators of effector responses (Ido1, Pd-l1). Protein levels of GZMB measured by ELISA were significantly increased in sADAM33 mice. Analysis of lymphocyte populations by flow cytometry identified an increased population of CD3-, NKp46+, KLRG1+ positive lymphocytes, which may represent an altered phenotype of innate lymphocyte populations in the airway.

The biology of innate lymphocytes is complex, but there is increasing support for their involvement in allergic disease. The altered phenotype of this cell population within the sADAM33 mice may play an important role in their increased susceptibility to allergic airways disease and warrants further investigation.

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More information

Published date: 16 September 2018
Venue - Dates: European Respiratory Society (ERS) International Congress 2018, , Paris, France, 2018-09-15 - 2018-09-19
Keywords: ADAM33, innate immune response, allergic asthma, airway inflammation

Identifiers

Local EPrints ID: 428129
URI: http://eprints.soton.ac.uk/id/eprint/428129
PURE UUID: 71c1b708-99d5-4c5f-bc79-d2af91ce1f6c
ORCID for Elizabeth R Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for Donna E Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 12 Feb 2019 17:30
Last modified: 10 Nov 2021 03:25

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Contributors

Author: Joanne, Freda Carmichael Kelly
Author: Yan Xu
Author: Jeffrey A. Whitsett
Author: Donna E Davies ORCID iD

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