嗜酸性粒细胞通过对造血系统再生的影响调控过敏性气道炎症的机制研究

Eosinophils (Eos) are the main inflammatory effector cells in allergic airway inflammation diseases, such as asthma. Currently, therapy targeting to Eos is still the crucial way to realize clinical control of asthma. Eos secrete different kinds of cytokines in local inflammatory tissues which mediate the asthma pathogenesis and clinical symptoms. However, the mechanisms of how Eos regulate asthmatic airway inflammation is currently unclear. We have recently observed that in the chicken ovalbumin (OVA)-induced mouse asthma model, Eos are involved in the regulation of hematopoietic system homeostasis, which is closely connected with hematopoietic differentiation and airway inflammation. The study was published on Cell Research (IF:15.606). Previous studies reported that allergic airway inflammation could not be successfully established in Eos-deficiency mice. We have used 5-Fluorouracil (5-FU) to establish a bone marrow suppression model with wild type (WT) and Eos-deficiency mice, and found that HSC regeneration and hematopoietic reconstitution were significantly prevented in Eos-deficiency mice. Based upon these findings, our study will deeply observe the mechanism of how Eos regulate the hematopoietic regeneration and airway inflammation. This study will provide new experimental base and a new therapeutic target to Eos for asthma control.

嗜酸性粒细胞（Eos）是过敏性气道炎症性疾病如支气管哮喘的主要炎症效应细胞，目前针对Eos的治疗仍然是哮喘临床控制的关键。Eos的炎症效应是由分泌的细胞因子导致的，与哮喘病理形成和临床症状密切相关，然而Eos在哮喘炎症中的调控机制尚不明确。我们课题组前期实验发现哮喘小鼠Eos对造血系统稳态的调控，与HSC的分化和炎症的发生有密切关系，相关结果发表于《Cell Research》杂志（IF：15.606）。且在Eos缺失的小鼠中不能构建哮喘的炎症病理改变；提示Eos可能通过影响造血系统来调控炎症的功能；我们在使用5-FU进行造血损伤和再生的实验，发现Eos缺失的小鼠存在明显的造血抑制，即Eos对造血的影响还表现为HSC再生方面。本研究拟在此基础上，进一步研究其中的具体机制，以及对哮喘炎症的影响，并为哮喘治疗新的靶点提供重要实验依据。

嗜酸性粒细胞（Eos）是哮喘气道炎症的主要效应细胞，目前靶向Eos的治疗是哮喘重症患者的关键治疗策略。前期项目主持人研究发现哮喘小鼠Eos增多可破坏造血干细胞稳态并正向促进Eos分化，是气道炎症调控的关键。本研究的主要内容为1）WT和Eos-null小鼠构建的哮喘模型的炎症分析；2）利用5氟尿嘧啶构建骨髓损伤和造血再生模型，探究嗜酸性粒细胞在造血重建中的重要作用；3）在WT和Eos-null小鼠骨髓中分选出造血干细胞，进行骨髓移植和造血重建，发现了缺失Eos后，造血干细胞表现出显著的重建障碍；4）通过转录组学以及骨髓上清的细胞因子蛋白质芯片检测和分析，明确了造血重建中，嗜酸性粒细胞影响造血干细胞再生和增殖的关键因子，IL-33。IL-33对嗜酸性粒细胞分化和哮喘炎症的关键调控作用已非常明确，本研究进一步明确了，IL-33和嗜酸性粒细胞二者形成了调控造血干细胞再生的正反馈调控机制，在哮喘炎症中同时发挥关键的调控作用。结合前期已发表的研究成果，项目主持人主要的研究发现在于探究了嗜酸性粒细胞在造血稳态中维持一定量、低水平存在的必要性。

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