Thymic stromal lymphopoietin and IL-33 modulate migration of hematopoietic progenitor cells in patients with allergic asthma

被引:74
作者
Smith, Steven G. [1 ]
Gugilla, Akash [1 ]
Mukherjee, Manali [1 ]
Merim, Kayla [1 ]
Irshad, Anam [1 ]
Tang, Wei [2 ]
Kinoshita, Takashi [2 ]
Watson, Brittany [2 ]
Oliveria, John-Paul [2 ]
Comeau, Mike [3 ]
O'Byrne, Paul M. [2 ]
Gauvreau, Gail M. [2 ]
Sehmi, Roma [1 ]
机构
[1] St Josephs Healthcare, Firestone Inst Resp Hlth, Hamilton, ON, Canada
[2] McMaster Univ, Dept Med, Asthma Res Grp, Hamilton, ON, Canada
[3] Amgen Inc, Inflammat Res, Seattle, WA USA
关键词
Hematopoietic progenitor cells; thymic stromal lymphopoietin; asthma; BONE-MARROW; EOSINOPHIL PROGENITORS; AIRWAY INFLAMMATION; SPUTUM EOSINOPHILIA; RESPONSES; DISEASE; CORTICOSTEROIDS; FACTOR-1-ALPHA; INTERLEUKIN-13; EXACERBATIONS;
D O I
10.1016/j.jaci.2014.12.1918
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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 1 alpha (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 alpha 1 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.
引用
收藏
页码:1594 / 1602
页数:9
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