基于CCR2/MCP-1通路探讨单核-髓源性抑制性细胞（M-MDSC）在慢性阻塞性肺疾病（COPD）中的作用机制

The impairment of immune cells plays pivotal role in the pathogenesis of COPD, especially for bacterial colonization and chronic inflammation in lower airway. Several studies showed the expansion of M-MDSC with immune suppression function in tumor or chronic inflammatory diseases. In the previous result, we found that a dramatic increase of M-MDSC in AECOPD patients with higher levels of chemotactic protein-1 receptor-2 (CCR2) than healthy controls. More importantly, we found that the proportion of M-MDSC showed a significantly correlation with some conventional markers of AECOPD patients, such as CRP. Based on that, a hypothesis is proposed: The number of circulating M-MDSC is increased in COPD model, and is recruited into lung tissue via CCR2/MCP-1 pathway. The infiltration of M-MDSC may participate in the immune impairment status in lung tissue. We will test the effect of M-MDSC on COPD mice by adoptive transferring M-MDSC into recipient mice with the same background which has deleted its own M-MDSC in vivo, and check whether the binding of CCR2/MCP-1 is committed to the migration of M-MDSC by CCR2-/- gene knockout mice. These research will shed light on the possible role of M-MDSC in the pathogenic mechanism of AECOPD, and provide a new way for the prevention and treatment of inflammatory responses in these patients.

免疫细胞功能缺陷是慢阻肺下呼吸道细菌定植、炎症迁延不愈的重要原因之一。研究发现:多种肿瘤或慢性炎症性疾病中可观察到单核-髓源性抑制性细胞（M-MDSC）的扩增，并发挥免疫抑制作用以负向调控免疫应答。我们前期研究发现：在慢阻肺（COPD）急性期患者外周血中，CCR2+的M-MDSC数量显著增加，且与多项炎症指标相关。基于以上研究，我们提出如下假说：COPD小鼠模型中M-MDSC显著扩增，其表面CCR2分子表达水平增加，在MCP-1趋化下向肺脏局部定向迁移，通过发挥免疫抑制作用参与肺脏局部免疫。我们拟通过磁珠分选技术纯化COPD小鼠M-MDSC，之后过继转移给已去除M-MDSC的同背景小鼠，结合体外实验探讨其在COPD致病中的作用；通过趋化实验及应用CCR2-/-全基因敲除小鼠，探讨M-MDSC是否依赖于MCP-1/CCR2途径向肺脏迁移，为揭示慢阻肺的致病机制提供理论依据。

气道慢性炎症是慢性阻塞性肺疾病（COPD）气道重塑的重要机制之一，COPD患者天然免疫细胞和获得性细胞均表现为部分表型或功能异常。研究表明，单核-髓源性抑制性细胞（M-MDSC）是一群具有免疫抑制活性的细胞群体。但目前对于M-MDSC在COPD中作用机制的研究鲜见报道。我们前期发现，COPD住院患者外周血中M-MDSC数量显著增加且与体多项炎症指标相关。据此，我们提出科学假说：COPD小鼠模型中M-MDSC显著扩增，借助于CCR2分子途径向肺脏局部定向迁移发挥免疫抑制作用，进而参与肺脏局部免疫。申请人拟通过磁珠分选技术纯化COPD小鼠M-MDSC，结合体外实验探讨其在COPD致病中的作用；借助于CCR2-/-全基因敲除小鼠和过继转移实验验证CCR2介导M-MDSC向肺脏迁移的机制，为揭示慢阻肺的致病机制提供理论依据。