We are interested primarily in Macrophages, but also dendritic cells and neutrophils.
These cells are phagcocytes, specialised blood cells, which ingest other cells (both microbial and self) as well as foreign particles.
Phagocytes have diverse roles during development, host defence, inflammation (mediation and resolution), wound healing, immune surveillance and alteration of the adaptive immune response.
Professional phagocytes are defined by their expression of a diverse array of receptors for recognising invading organisms such as bacteria and fungi, dead and dying cells, abnormal host cells and environmental particles. These receptors are ‘opsonic’, such as the Fc and complement receptors, and ‘non-opsonic’, such as the Toll-like receptors, and specific cell surface lectins.
Our research is primarily focused on the fundamental aspects of phagocyte biology, such as the receptors used to recognise pathogens, the signalling molecules involved in the subsequent downstream cellular activation events and fundamental aspects of cell biology such as the regulation of apoptosis or cell renewal.
Understanding, how phagocytes respond to specific challenges presents an opportunity to manipulate the behaviour of cells at the very heart of innate and adaptive immunity.
Study of the ‘macrophage-lineage’ encompases a broad variety of cells including peripheral monocytes, tissue resident macrophages and dendritic cells and inflammatory moncoytes with characteristics of macrophages and dendritic cells.
Macrophages are derived from distinct sources. Circulating monocytes, derived from hematopoiesis in the bone marrow of the adult, give rise to a variety of macrophages throughout the body, both tissue resident cells such as the intestinal macrophages and osteoclasts as well as inflammatory macrophages and monocyte derived dendritic cells.
Monocytes originate in the bone marrow from a common myeloid progenitor that is shared with neutrophils, and they are then released into the peripheral blood, where they circulate for several days before entering tissues and replenishing select tissue macrophage populations or following inflammatory cues to sites of disease or injury.
The morphology of mature monocytes in the peripheral circulation is heterogeneous, and these cells constitute approx. 5–10% of peripheral-blood leukocytes in humans. They vary in size and have different degrees of granularity and varied nuclear morphology.
Tissue macrophages have a broad role in the maintenance of tissue homeostasis, through the clearance of senescent cells and the remodelling and repair of tissues after inflammation, although they are perhaps best known for their roles as the tissues immune sentinels. Whilst until quite recently considered to be derived from monocytes, it is now clear that many tissue resident macrophages are derived prenatally.
For examples, Microglia, the macrophages of the brain, are seeded into the tissue by yolk sac macrophages and Langerhans cells in the skin are derived both from yolk sac macrophages and from fetal liver hematopoeisis. These cells are seeded prenatally and then expanded postnatally and maintained in the adult by local proliferative renewal of the mature cells without the need for input from the adult bone marrow. In contrast, other populations such as the intestinal macrophages are renewed by peripheral monocyte influx.
Macrophages exhibit a very high degree of heterogeneity, which is consistent with their discrete anatomical compartmentalization and the specialized functions they conduct in those specific niches. The factors that control this specialization are an area of significant interest.
- McDonald, J. U. et al. 2011. In vivo functional analysis and genetic modification of in vitro-derived mouse neutrophils. The FASEB Journal 25 (6), pp.1972-1982. (10.1096/fj.10-178517)
- Davies, L. C. et al. 2011. A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. European Journal of Immunology 41 (8), pp.2155-2164. (10.1002/eji.201141817)
- Liddiard, K. et al. 2011. Macrophage heterogeneity and acute inflammation. European Journal of Immunology 41 (9), pp.2503-2508. (10.1002/eji.201141743)
- Rosas, M. et al. 2011. Hoxb8 conditionally immortalised macrophage lines model inflammatory monocytic cells with important similarity to dendritic cells. European Journal of Immunology 41 (2), pp.356-365. (10.1002/eji.201040962)
- Robinson, M. J. et al., 2009. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. Journal of Experimental Medicine 206 (9), pp.2037-2051. (10.1084/jem.20082818)
- Rosas, M. et al. 2008. The induction of inflammation by dectin-1 in vivo is dependent on myeloid cell programming and the progression of phagocytosis. Journal of Immunology 181 (5), pp.3549-3557.
- Taylor, P. R. et al. 2007. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nature Immunology 8 (1), pp.31-38. (10.1038/ni1408)
- McGreal, E. P. et al. 2006. The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 16 (5), pp.422-30. (10.1093/glycob/cwj077)
- Taylor, P. R. et al. 2004. The role of SIGNR1 and the beta-glucan receptor (dectin-1) in the nonopsonic recognition of yeast by specific macrophages. The Journal of Immunology 172 (2), pp.1157-1162.
- Taylor, P. R. et al. 2002. The beta-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages. Journal of Immunology 169 (7), pp.3876-3882.
- Brown, G. D. et al., 2002. Dectin-1 is a major beta-glucan receptor on macrophages. Journal of Experimental Medicine 196 (3), pp.407-12. (10.1084/jem.20020470)
Dectin-1 and immune response to fungi
Dectin-1 is an NK-like C-type lectin-like receptor specific for beta-(1,3)-glucans.We have shown that it is primarily expressed by myeloid cells, such as neutrophils, monocytes, macrophages and dendritic cells where it functions as a major receptor for both soluble and particulate beta-(1,3)-glucans. We have continued to demonstrate that the receptor is non-redundant in vivo in fungal host defence, but it is part of an extensive network of pattern recognition receptors involved concurrently in the recognition of fungi with distinct and overlapping functions.
Its expression and function is regulated by the cellular activation state and the inflammatory or steady-state tissue environment and by the ability of the phagocyte to complete the engulfment of the pathogen once recognised.
We aim to continue to understand how dectin-1 regulates cellular activation and controls inflammatory responses as a model of an emerging family Syk-activating pattern recognition receptors.
Dectin-2 and immune response to fungi
We have demonstrated that dectin-2 is a C-type lectin receptor specific for carbohydrates with a ‘complex mannose-like’ structure and as such is capable of recognising carbohydrates on pathogens such as fungi and mycobacterium.
We generated specific monoclonal antibodies against dectin-2, which have shown that it is primarily expressed by macrophages and dendritic cells.
The use of these monoclonal antibodies as blocking agents has indicated that dectin-2 plays important roles alongside dectin-1 in the regulation of immune responses during fungal infections.
We aim to further elucidate the role of dectin-2 in cellular activation, host defence and immunity.
Conditional immortalisation of myeloid-precursors to model innate immunity
As part of our commitment to the replacement, refinement and reduction of animal use in experimental research we have been developing published protocols for the study of innate immune responses by neutrophils and macrophages, by conditional-immortalisation of the their precursors.
The ease with which these cells can be developed and genetically-modified has already impacted on the use of animals in research and is providing a cornerstone onto which new experimental models are being built to address the roles of select pathogen recognition systems in cellular activation events.
Macrophage biology in homeostasis and disease
We have a general interest in the biology of macrophages during homeostasis and disease and are using novel approaches to identify key pathways and processes that can be manipulated to alter macrophage biology in the living organism for possible therapeutic benefit.
Recently, we have shown that tissue resident macrophages in vascular tissues are capable of self-renewal by local proliferation. By applying specific measures of mitosis, we have monitored tissue macrophage proliferation during newborn development, adulthood and acute resolving inflammation in young adults.
Despite the vascular nature of the tissue and ease of peripheral leukocyte entry, tissue macrophages in the newborn increase in number by local proliferation. On the contrary, in the adult, tissue macrophage proliferation is considerably reduced and most likely provides homeostatic control of cell numbers.
Importantly, during an acute inflammatory response, when substantial numbers of inflammatory macrophages are recruited from the circulation, tissue-resident macrophages survive and then undergo a transient and intense proliferative burst in situ to repopulate the tissue.
Our data indicate that local proliferation is a general mechanism for the self sufficient renewal of tissue macrophages during development and acute inflammation and not one restricted to non-vascular tissues, which has implications for the therapeutic modulation of macrophage activity during the resolution of inflammation.
Collaborative and Redundant Roles of CLRs in Anti-Fungal Immunity
Myeloid cells such as macrophages, dendritic cells and neutrophils use cell surface receptors to recognize invading fungal pathogens. Various C-type lectin-like receptors including Dectin-1, Dectin-2, Mincle, Mannose receptor and DC-SIGN are involved in the recognition of various fungal cell-wall components such as beta-glucans and mannans.
These receptors concurrently induce an inflammatory response upon recognition of fungal pathogens. Therefore, anti-fungal immune responses are complex, involving a highly co-ordinated response from multiple receptors.
I aim to determine how these receptors function individually and how they work together/collaborate to induce the co-ordinated anti-fungal immune response. To achieve this aim, I will generate novel models to fully dissect the role of these receptors during anti-fungal responses.