The function of eosinophils in bone remodelling

骨稳态基本上由免疫系统控制。虽然适应性免疫系统的细胞和介质如T细胞和抗体对骨的影响已经得到很好的表征，但对先天免疫细胞在控制骨稳态中的作用知之甚少。令人惊讶的是，在先天免疫细胞中，嗜酸性粒细胞的作用似乎特别有趣。除了它们在宿主防御寄生虫中的作用外，嗜酸性粒细胞在控制组织稳态中的作用越来越受到重视。例如，嗜酸性粒细胞通过促进米色脂肪的产生来控制脂肪和温度的稳态。此外，我们和其他人已经证明嗜酸性粒细胞通过促进抗炎巨噬细胞的分化参与慢性炎症如关节炎的消退。因此，嗜酸性粒细胞具有有趣的功能方面，使其在控制骨稳态中发挥积极作用，特别是通过影响破骨细胞的分化。使用基因工程小鼠模型的初步数据支持这一概念，并显示嗜酸性粒细胞的缺乏导致骨丢失加剧，而嗜酸性粒细胞数量的增加导致骨量增加。我们推测嗜酸性粒细胞的这种骨保护作用基本上是基于它们的细胞因子产生模式，其中包括IL-4-一种众所周知的破骨细胞生成的负调节因子。因此，本申请的目的是：（1）表征缺乏嗜酸性粒细胞的小鼠的骨表型和破骨细胞分化（δ dblGATA小鼠）和高嗜酸性粒细胞增多症小鼠中（2）分析嗜酸性粒细胞在免疫激活、衰老和绝经等不同病理性骨丢失模型中的作用; 3）破译嗜酸性粒细胞调节破骨细胞分化的分子机制;（4）通过确定人体系统中嗜酸性粒细胞对破骨细胞的影响，将我们的发现转化为人类。总之，这些实验将描述嗜酸性粒细胞在骨稳态中的作用。

Bone homeostasis is essentially controlled by the immune system. While the influence of cells and mediators of the adaptive immune system such as T cells and antibodies on bone has been well characterized, much less is known about the role of innate immune cells in controlling bone homeostasis. Surprisingly, among innate immune cells the role eosinophils seems particularly interesting. Apart from their role in host defence against parasites eosinophils are increasingly appreciated for their role in controlling tissue homeostasis. For instance, eosinophils control fat and temperature homeostasis by promoting the generation of beige fat. Furthermore, we and others have demonstrated that eosinophils are involved in the resolution of chronic inflammation such as arthritis by promoting the differentiation of anti-inflammatory macrophages. Hence, eosinophils hold interesting functional aspects that predispose them to play an active role in controlling bone homeostasis, especially by affecting the differentiation of osteoclasts. Preliminary data using genetically engineered mouse models support this concept and show that absence of eosinophils leads to exacerbated bone loss, while an increase in eosinophil numbers results in increased bone mass. We speculate that this bone protective effect of eosinophils is essentially based on their cytokines production pattern, which includes IL-4- a well-known negative regulator of osteoclastogenesis. Hence, the aim of this application is: (1) to characterize the bone phenotype and osteoclast differentiation in mice lacking eosinophils (delta dblGATA mice) and in mice with hyper eosinophilia (IL-5tg mice); (2) to analyse the importance of eosinophils in different models of pathological bone loss induced by immune activation, ageing and menopause; 3) to decipher the molecular mechanism how eosinophils regulate osteoclast differentiation; and (4) to translate our finding to humans by determining the effects of eosinophils on osteoclasts in the human system. In summary, these experiments will delineate the role of eosinophils in bone homeostasis.