Targeting tissue macrophage generation as a mechanism to modulate the resolution of inflammation.

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Tissue resident macrophages are white blood cells that are scattered throughout and live in the tissues of our body. They are at the frontline of host defense against infection in the tissue and play important roles in maintaining the normal function of the tissue itself. After an infection, macrophages are also recruited to the tissue from the blood, arriving as blood monocytes that originate from the bone marrow and turn into macrophages upon arrival. Our recent studies highlight the quite distinct origins of tissue resident and monocyte-derived macrophages. They show differences in gene expression that probably reflect not just their distinct functional programming, but also the mechanism by which tissue macrophages are programmed to survive for long periods in the tissue, and to self-renew. By manipulating specific subsets of macrophages we aim to bias responses to infection and wound repair to promote beneficial outcomes. Our proposed studies would be first proof-of-principle experiments that would examine a new avenue of research directed at the control of infection and tissue damage.

Technical Summary

We have identified transcription factors normally associated with development, cellular proliferation, differentiation and renewal that are selectively expressed in tissue resident macrophages (as opposed, for example, to monocyte-derived macrophages). We have shown that tissue resident macrophages are a self-renewing population that is independent of bone marrow-derived monocytic precursors. Since these transcription factors are anticipated or are known to be lethal when targeted to generate null alleles in mice, we will generate myeloid specific knockouts using the lysozyme M-Cre mice (Lyz2-Cre). These mice will be characterized for abnormalities in macrophage development and, assuming the mice are not fundamentally defective in tissue macrophages, in the response to inflammatory challenges. These challenges are designed to test their self-renewal and inflammatory responses at the same time. If feasible (depending on the severity of the impact of conditional-ablation on the macrophage lineage) the cells will also be tested ex vivo to establish if abrogation of these specific transcription factors alters phenotype in a way that fundamentally impacts on inflammatory responses, or is more restricted to roles in macrophage development and renewal. We believe that these studies will test the principle that we can specifically manipulate the existence and/or renewal of tissue resident macrophages, with only secondary impacts on the monocyte-derived lineage, and that this may provide a novel avenue to alter tissue homeostasis, host defense and the resolution of inflammation for therapeutic benefit.

Planned Impact

The main beneficiary with immediate impact would be academia, including academia outside the applicants immediate professional circle. This is because the research will provide basic insights into tissue homeostasis in general and to any disease pathology involving macrophages, which broadens the scope to other fields, for example, autoimmunity, allergy and tumour biology.

A secondary beneficiary with medium term impact would be the Industrial and pharmaceutical sector. Several of the applicants have collaborative or other associations with industry and are well positioned to exploit any novel intellectual property. We would anticipate that the output from this research would lead fairly rapidly to additional industrial collaborations based on our past experience and existing collaborations. Intellectual property would be appropriately protected for exploitation and several of the applicants have experience in this area (see 'Pathways to Impact' for more information)

In the longer term this work should directly benefit patients with infectious or inflammatory diseases as macrophage phenotype and behaviour is central to many disease outcomes. The application of these studies directly to patient samples will ensure that the work is relevant to human disease. Characterisation of macrophage activation and developmental pathways will increase understanding and reveal pathways that can be exploited to reduce the impact of inflammatory and infectious diseases.

The School of Medicine at Cardiff is very actively engaged in public engagement (see 'Pathways to Impact' for more information). We would hope that the continued involvement of principle investigators, including the lead applicant, would continue to inspire young people towards a career in science and show the research in Cardiff, and the UK as a whole, as internationally leading.

Publications

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Davies LC (2015) Tissue-resident macrophages: then and now. in Immunology

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Davies LC (2013) Tissue-resident macrophages. in Nature immunology

 
Description Cardiff University PhD Studentship
Amount £75,000 (GBP)
Organisation Cardiff University 
Department School of Medicine
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 09/2016
 
Description Cardiff University/MRC DTG PhD studentship
Amount £68,000 (GBP)
Organisation Cardiff University 
Department School of Medicine
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 09/2016
 
Description MRC DTP Studentship
Amount £75,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2015 
End 03/2019
 
Description Ser Cymru Capital Equipment Award
Amount £225,000 (GBP)
Organisation Health and Care Research Wales 
Sector Public
Country United Kingdom
Start 03/2016 
End 02/2021
 
Description Wellcome Investigator Award
Amount £1,414,000 (GBP)
Funding ID 107964/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 01/2021
 
Title g6set 
Description Microarray dataset 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact too soon, including in PMID24762537 
 
Description G6 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution We led this research and conducted the majority of the work.
Collaborator Contribution Provided some advice and advanced analytical assistance
Impact PMID: 24762537
Start Year 2007
 
Description G6 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution We led this research and conducted the majority of the work.
Collaborator Contribution Provided some advice and advanced analytical assistance
Impact PMID: 24762537
Start Year 2007
 
Description Infl 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, experimental support provision of analysis macros
Collaborator Contribution They led on this project
Impact PMID: 25175678
Start Year 2012
 
Description fib 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, experimental support, some experiments and data.,
Collaborator Contribution They led this research.
Impact PMID: 24412616
Start Year 2009
 
Description Online news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Supply of notable scientific and otherwise (e.g. human interest) news stories from Cardiff Immunologists to a regularly updated immunology website.

This activity helps create the internet face of cardiff immunologists withan ima to increasing profile and aiding in recruitment.
Year(s) Of Engagement Activity 2009,2010,2011,2012
 
Description Open days - school visitors 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The School of Medicine host a Science day, which in 2009 was considered in the top 3 of such events. This involves talks and demonstrations to ~500 A levels students. I have now taken part in this scheme, primarily in 2009 in a publicity capacity ensuring external coverage (including coverage by the British Society of Immunology). This has continues on an annual basis

This event creates a deal of publicity for medical research in Cardiff and serves as a stimulus for the recruitment of future researchers and doctors.
Year(s) Of Engagement Activity 2009,2010,2011,2013