Macrophages can be broadly divided into two phenotypically and functionally distinct subsets, classically activated macrophages (CAM) and alternatively activated macrophages (AAM). In contrast to CAM, which promote inflammation and kill intracellular pathogens, AAM regulate inflammation, promote wound healing and tissue repair, and contribute to the clearance of helminth parasites. Since macrophages play a role in numerous inflammatory diseases, this dichotomy in macrophage function may provide an opportunity to influence disease outcomes by manipulating these different subsets. However, identifying potential targets for manipulation will require a more complete understanding of the processes that control differentiation and accumulation of CAM and AAM in both acute and chronic inflammation. Although the origins of CAM have been studied in various infection models, the origins of AAM are incompletely understood and have not been examined during chronic T helper 2 (Th2) infection. We propose to use infection with the parasitic helminth Schistosoma mansoni as a model of both acute and chronic Th2 infection to examine the origins and mechanisms of differentiation of AAM. It has been proposed that AAM can be derived either from monocyte precursors or through local IL-4-dependent proliferation of tissue macrophages, independently of monocytes. The ability of macrophages to differentiate into AAM through proliferation may represent an important mechanism to maintain AAM during tissue repair and healing while inflammation is being down-regulated, leading to a decrease in monocyte recruitment. Since immune down-regulation is a feature of chronic S. mansoni infection, we hypothesize that monocyte recruitment may contribute to accumulation of AAM during acute infection, but that proliferation may be important for maintaining AAM during chronic infection. To test this hypothesis, we will use a combination of flow cytometry and intravital microscopy to determine if monocytes and/or proliferation of local macrophages contribute to accumulation of AAM within the hepatic granulomas of S. mansoni infected mice. In addition, we will determine the roles of IL-4 and CD4+ Th2 cells in inducing or maintaining AAM through monocyte recruitment and/or proliferation during acute and chronic infection. By defining the cellular sources and mechanisms required for accumulation of AAM during acute and chronic infection, we will increase our understanding of how acute versus chronic inflammation affects the induction and maintenance of AAM.
Alternatively activated macrophages are important for limiting inflammation and repairing tissue damage. Understanding the factors that control differentiation of these cells represents a critical step towards developing therapeutics that could affect the outcome of inflammatory diseases by selectively reducing or enhancing the functions of these cells. We aim to understand the cellular sources and factors that control differentiation of alternatively activated macrophages in the context of acute and chronic infection with the parasitic worm Schistosoma mansoni.
|Gundra, Uma Mahesh; Girgis, Natasha M; Ruckerl, Dominik et al. (2014) Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood 123:e110-22|
|Girgis, Natasha M; Gundra, Uma Mahesh; Loke, P'ng (2013) Immune regulation during helminth infections. PLoS Pathog 9:e1003250|