Grant: Discovery Grants Program - Individual

As mononuclear phagocytes, tissue macrophages (M?) exhibit diverse and divergent activities in response to tissue damage. These functions are expected to be executed by at least two different subtypes of polarized M?: pro-inflammatory M1 M?, which express tissue-destructive activities, and anti-inflammatory M2 M?, which exhibit tissue-reparative activities. However, although the initial M? maturation process is well established, the regulating mechanisms involved in terminal M? differentiation remain to be clearly elucidated. To address this question, we have chosen uterine M? as experimental model because they are abundant within the endometrium and their number and phenotype are subjected to change in response to uterine or embryonic factors. During early pregnancy, uterine M? are locally modified to exhibit an immunosuppressive phenotype and to perform pregnancy-associated functions. Of note, some key pregnancy-associated factors are also involved in M? survival, activation and function. This suggests that uterine factors can also regulate stable M? polarization during early gestation via activation of specific signalling pathways in M?. The fundamental relevance of our studies is based on the fact that regulation of M? polarization is required for normal physiological processes, mainly the onset and the resolution of inflammation, but also to avoid inappropriate M? activation and thus lead to pathological functions. Using the mouse as a model, our long-term goal is to better understand and document the physiology of the uterine immune system by defining the molecular basis for physiological responses of resident and recruited leukocytes in the pregnant uterus. Specifically, we propose to determine the molecular mechanisms involved in M? differentiation during early pregnancy by investigating the effects of pregnancy-associated factors on M? polarization and plasticity in vivo and in vitro. It is hoped that the forthcoming information will generate new working hypothesis and concepts to better define the role of M?-mediated activities in other physiological or pathological processes.