胸腺基质淋巴细胞生成素和 IL-33 调节过敏性哮喘患者造血祖细胞的迁移。
Thymic stromal lymphopoietin and IL-33 modulate migration of hematopoietic progenitor cells in patients with allergic asthma.
机构信息
Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, Ontario, Canada.
Asthma Research Group, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
出版信息
J Allergy Clin Immunol. 2015 Jun;135(6):1594-602. doi: 10.1016/j.jaci.2014.12.1918. Epub 2015 Feb 3.
BACKGROUND
Thymic stromal lymphopoietin (TSLP) and IL-33 are considered important initiators of type 2 immunity. In asthmatic patients allergic inflammatory responses are associated with increased lung homing of bone marrow-derived CD34(+) hematopoietic progenitor cells (HPCs), which include eosinophil lineage-committed progenitor cells. In this study we investigated the role of TSLP and IL-33 in the recruitment of progenitor cells to the airways in asthmatic subjects.
OBJECTIVES
We sought (i) to examine the effect of allergen inhalation challenge on expression levels of receptors for TSLP (thymic stromal lymphopoietin receptor [TSLPR] and CD127) and IL-33 (ST2) and (ii) investigate the functional effects of these cytokines on HPCs.
METHODS
Consenting patients with mild atopic asthma (n = 19) with an FEV1 of 70% or greater and methacholine PC20 of 16 mg/mL or less were recruited. Blood- and sputum-extracted progenitors were phenotyped by flow cytometry before and 24 hours after allergen challenge. Functional responses, including cytokine production and migration to TSLP and IL-33, were assessed in vitro.
RESULTS
Significant increases in mature eosinophil, HPC, and eosinophil lineage-committed progenitor cell counts in sputum were observed 24 hours after allergen and were associated with a significant allergen-induced increase in HPCs expressing TSLPR, CD127, and ST2. Pre-exposure to TSLP and IL-33 primed the migration of HPCs to a potent progenitor cell chemoattractant, stromal cell-derived factor 1α (CXCL12). Incubation with TSLP and IL-33 stimulated significant production of IL-5 and IL-13, but not IL-4, by HPCs. This priming effect was inhibited by blocking antibodies to TSLPR and ST2, respectively, and IL-13 receptor α1 in both scenarios.
CONCLUSIONS
In allergic asthmatic responses increased lung homing of HPCs may be orchestrated by TSLP and IL-33 through an IL-13-dependent axis.
背景
胸腺基质淋巴细胞生成素 (TSLP) 和 IL-33 被认为是 2 型免疫的重要启动子。在哮喘患者中，过敏炎症反应与骨髓来源的 CD34(+)造血祖细胞（HPC）向肺部的归巢增加有关，其中包括嗜酸性粒细胞系定向祖细胞。在这项研究中，我们研究了 TSLP 和 IL-33 在哮喘患者气道中祖细胞募集中的作用。
目的
我们试图 (i) 检查过敏原吸入挑战对 TSLP（胸腺基质淋巴细胞生成素受体 [TSLPR] 和 CD127）和 IL-33（ST2）受体表达水平的影响，以及 (ii) 研究这些细胞因子对 HPC 的功能影响。
方法
同意参加研究的轻度特应性哮喘患者（n=19），FEV1 为 70%或更高，且乙酰甲胆碱 PC20 为 16mg/mL 或更低。在过敏原挑战之前和之后 24 小时，通过流式细胞术对血液和痰液提取的祖细胞进行表型分析。在体外评估包括细胞因子产生和向 TSLP 和 IL-33 的迁移在内的功能反应。
结果
在过敏原后 24 小时观察到痰中成熟嗜酸性粒细胞、HPC 和嗜酸性粒细胞系定向祖细胞计数的显著增加，这与 HPC 表达 TSLPR、CD127 和 ST2 的显著过敏原诱导增加相关。TSLP 和 IL-33 的预先暴露启动了 HPC 向强效祖细胞趋化因子基质细胞衍生因子 1α（CXCL12）的迁移。TSLP 和 IL-33 的孵育刺激 HPC 产生显著的 IL-5 和 IL-13，但不是 IL-4。这种启动效应分别被 TSLPR 和 ST2 的阻断抗体以及两种情况下的 IL-13 受体 α1 抑制。
结论
在变应性哮喘反应中，HPC 的肺部归巢增加可能是由 TSLP 和 IL-33 通过 IL-13 依赖的轴来协调的。
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