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

组织巨噬细胞(M？)作为单核巨噬细胞，对组织损伤的反应具有多样性和差异性。这些功能预计至少由两种不同的极化M？执行：表达组织破坏性活动的促炎性M1 M？和表现组织修复活性的抗炎性M2 M？然而，尽管最初的M？成熟过程已被很好地建立，但参与M？末端分化的调节机制仍有待阐明。为了解决这个问题，我们选择子宫肌动蛋白作为实验模型，因为它们在子宫内膜中含量丰富，其数量和表型会随着子宫或胚胎因素的变化而变化。在怀孕早期，子宫M？被局部修饰，以表现出免疫抑制表型并执行与妊娠相关的功能。值得注意的是，一些与妊娠相关的关键因素也与M？的存活、激活和功能有关。这表明，子宫因素也可以通过激活M？中的特定信号通路来调节妊娠早期稳定的M？极化。我们研究的基本相关性是基于这样一个事实，即正常的生理过程需要调节M？极化，主要是炎症的开始和消退，但也是为了避免不适当的M？激活，从而导致病理功能。以小鼠为模型，我们的长期目标是通过定义妊娠子宫中常驻和招募的白细胞的生理反应的分子基础，更好地了解和记录子宫免疫系统的生理学。具体地说，我们建议通过研究妊娠相关因素在体内和体外对M？极化和可塑性的影响来确定参与M？分化的分子机制。希望即将到来的信息将产生新的工作假说和概念，以更好地定义M？介导的活动在其他生理或病理过程中的作用。

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.