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

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.

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.

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.