Steve Jenkins is investigating the functional diversity of myeloid cells in tissue homeostasis and immune regulation, with a major focus on the mechanisms that maintain tissue resident macrophages under steady state and inflammatory conditions.
Myeloid cells including macrophages and dendritic cells exhibit a vast diversity. Many tissues contain at least two populations of macrophages in addition to distinct dendritic cell populations, yet we still don't fully understand why such diversity exists. The focus of my lab is to identify the functional differences between the numerous co-existing tissue macrophage populations, and to identify the mechanisms through which these different populations are maintained.
In particular, it has recently been discovered that certain populations of resident macrophages, such as Kuppfer cells and alveolar macrophages, are not replenished by blood monocytes but self-renew in order to maintain population size. Whether these populations are derived from tissue stem cells, or if they have limited regenerative capacity, remains to be determined. Furthermore, it is unlcear if reaching any such limit may have consequence for the outcome of inflammatory disease.
By addressing these questions, we aim to identify novel pathways to control inflammation and to manipulate macrophage functions and numbers during disease.
Macrophages (Mφ) and dendritic cells (DC) have a plethora of functions central to the maintenance of healthy tissue. Reflecting this, Mφ and DC encompass highly heterogeneous populations of cells. The diversity of tissue DC has been revealed through identification of population-specific precursor cells, transcription factors, and growth factors, while the recruitment and differentiation of blood monocytes has long been considered to maintain tissue Mφ density. Emerging evidence however suggests that the predominant population of 'resident' Mφ in many tissues may not rely upon recruitment of monocytes or other hematopoietic-derived precursors, but rather exist by longevity, self-renewal or generation from an as yet unidentified tissue stem cell. The mechanisms that maintain the autonomy of tissue resident macrophages thus remain to be determined.
Cells that appear to be derived from recruited monocytes are also present in tissues alongside 'resident' Mφ and DC, although whether these recruited cells represent a functionally distinct population or an intermediate stage to these endpoints is unclear. Furthermore, either population of Mφ ('resident' vs 'recruited') may predominate during disease depending upon the type or stage of inflammatory insult. We have shown that during infection with nematode worms, the resident peritoneal and pleural macrophages undergo greatly elevated proliferation under the action of the cytokine IL-4 in order to generate macrophages locally without need for monocyte recruitment.
Using lineage-tracing and in vivo manipulation methods, the comparative regulation, function and plasticity of resident and recruited populations are being interrogated in both homeostasis and a range of inflammatory disease models established at College of Medicine and Veterinary Medicine.
Project 1: The parameters that regulate autonomy of tissue resident Mφ
Project 2: The function and regulation of monocyte-derived tissue resident Mφ