Studies of macrophage behavior changes in response to pregnancy-associates factors

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As mononuclear phagocytes, tissue macrophages (MØ) 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 MØ: pro-inflammatory M1 MØ, which express tissue-destructive activities, and anti-inflammatory M2 MØ, which exhibit tissue-reparative activities. However, although the initial MØ maturation process is well established, the regulating mechanisms involved in terminal MØ differentiation remain to be clearly elucidated. To address this question, we have chosen uterine MØ 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 MØ 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 MØ survival, activation and function. This suggests that uterine factors can also regulate stable MØ polarization during early gestation via activation of specific signalling pathways in MØ. The fundamental relevance of our studies is based on the fact that regulation of MØ polarization is required for normal physiological processes, mainly the onset and the resolution of inflammation, but also to avoid inappropriate MØ 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 MØ differentiation during early pregnancy by investigating the effects of pregnancy-associated factors on MØ 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 MØ-mediated activities in other physiological or pathological processes.