CD169+组织驻留巨噬细胞对于炎症反应的负性调控作用

作为天然免疫的重要参与者，巨噬细胞主要通过分泌多种炎性介质来发挥促进炎症反应的作用。有趣的是，我们发现利用CD169-DTR小鼠模型去除CD169+巨噬细胞后，不同刺激条件下小鼠多个器官里反而会产生更强的炎症反应。影像学及单细胞测序分析显示是剩下的CD169-巨噬细胞在分泌大量的炎性因子。更进一步，分选出的CD169+巨噬细胞在体外也具备抑炎作用。这些数据表明，不同于已知的在免疫反应中由细胞因子诱导产生的M2型巨噬细胞，组织里天然存在一群CD169+“调节性巨噬细胞”来抑制过度的炎症反应。因此，我们将研究如下科学问题：1. CD169+巨噬细胞的具体表型及其在炎症反应中的负性调控作用；2. CD169+巨噬细胞发挥抑炎作用的具体分子机制；3. CD169+巨噬细胞在细菌感染疾病模型中对机体的保护性作用。阐明这些问题将让我们更好地认识巨噬细胞的异质性，并为治疗炎症相关疾病提供新的思路。

As a major participant in innate immunity, macrophages are mainly considered to be pro-inflammatory upon stimulation by secretion of a variety of cytokines and chemokines. However, our new data showed very interestingly that transient depletion of a subset of tissue resident macrophages in CD169-DTR mice resulted in much higher inflammation in a bunch of tissues in response to multiple stimuli. The imaging and single cell sequencing data showed that it is the remaining CD169- tissue resident macrophages producing substantially elevated inflammatory cytokines. Furthermore, the isolated CD169+ macrophages can exert anti-inflammatory functions in vitro. These findings suggest that, different from M2 macrophages, which require type 2 cytokines for differentiation, there already exists a population of CD169+ "regulatory macrophages" in the tissues for suppressing excessive inflammatory responses. Therefore, we would like to address the following questions: 1 The role of CD169+ tissue resident macrophages in the negative regulation of inflammatory responses and their specific phenotypes; 2 The mechanisms underlyling CD169+ macrophage suppressive role in inflammatory responses; 3 The protective role of CD169+ macrophages in bacterial infection disease model. Taken together, our study will broaden our understanding of the heterogeneity of tissue resident macrophages and provide new strategies for the treatment of inflammation-associated diseases.