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Adam33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice

Adam33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
Adam33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
Rationale: ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an Adam33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. Wehave found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood.
Methods: to study how the response to HDM is altered by loss of Adam33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next genera- tion RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associ- ated with the differential response to HDM between KO and WT mice.
Results: control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including Adam33, FDR p<0.05). Differential expression analysis comparing WT saline to HDM treated mice identified the transcriptional profile of the ‘normal’ response to HDM. The KO response demonstrated a degree of similarity with the WT response (62% of up-regulated genes, 51% of down-regulated gene), including upregulation of hallmark asthma genes IL13, IL5 and Ccl11. However, there were also distinct groups of genes modulated only in the WT or the KO in response. Further analysis of the genes identified a predominantly metabolic gene signature, with a particular emphasis on oxidative phosphorylation, where com- ponents of the mitochondrial electron transport chain were modulated in opposing directions in the HDM-challenged WT and KO mice.
Discussion: the alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and Adam33 KO mice.
ADAM33, knockout, house dust mite, metabolic transcriptional profile, RNA-Sequencing
0040-6376
A17
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Bell, Joseph, Alan
9ce5c105-543f-40c2-883a-26643c194638
Holgate, Stephen T
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Xu, Yan
c9c742b1-4b1c-4720-956b-12928519e4d0
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna
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
Bell, Joseph, Alan
9ce5c105-543f-40c2-883a-26643c194638
Holgate, Stephen T
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Xu, Yan
c9c742b1-4b1c-4720-956b-12928519e4d0
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe

Kelly, Joanne, Freda Carmichael, Davies, Elizabeth R, Bell, Joseph, Alan, Holgate, Stephen T, Xu, Yan, Whitsett, Jeffrey A., Davies, Donna and Haitchi, Hans Michael (2018) Adam33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice. Thorax, 73 (Supplement 4), A17, [73(Suppl 4): A1-A282]. (doi:10.1136/thorax-2018-212555.33).

Record type: Meeting abstract

Abstract

Rationale: ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an Adam33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. Wehave found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood.
Methods: to study how the response to HDM is altered by loss of Adam33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next genera- tion RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associ- ated with the differential response to HDM between KO and WT mice.
Results: control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including Adam33, FDR p<0.05). Differential expression analysis comparing WT saline to HDM treated mice identified the transcriptional profile of the ‘normal’ response to HDM. The KO response demonstrated a degree of similarity with the WT response (62% of up-regulated genes, 51% of down-regulated gene), including upregulation of hallmark asthma genes IL13, IL5 and Ccl11. However, there were also distinct groups of genes modulated only in the WT or the KO in response. Further analysis of the genes identified a predominantly metabolic gene signature, with a particular emphasis on oxidative phosphorylation, where com- ponents of the mitochondrial electron transport chain were modulated in opposing directions in the HDM-challenged WT and KO mice.
Discussion: the alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and Adam33 KO mice.

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More information

Published date: 5 December 2018
Venue - Dates: British Thoracic Society Winter Meeting 2018, QEII Centre Broad Sanctuary Westminster SW1P 3EE, London, United Kingdom, 2018-12-05 - 2018-12-07
Keywords: ADAM33, knockout, house dust mite, metabolic transcriptional profile, RNA-Sequencing

Identifiers

Local EPrints ID: 428132
URI: http://eprints.soton.ac.uk/id/eprint/428132
ISSN: 0040-6376
PURE UUID: bf9cd2d8-b594-4b32-8e4c-8d235ba61145
ORCID for Elizabeth R Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for Donna 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: Joseph, Alan Bell
Author: Yan Xu
Author: Jeffrey A. Whitsett
Author: Donna Davies ORCID iD

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