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

J Allergy Clin Immunol. 2015 Jun;135(6):1594-602. doi: 10.1016/j.jaci.2014.12.1918. Epub 2015 Feb 3.

Abstract

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.

Keywords: Hematopoietic progenitor cells; asthma; thymic stromal lymphopoietin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adult
  • Allergens / pharmacology
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Cell Movement / drug effects
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / immunology
  • Cytokines / genetics
  • Cytokines / immunology*
  • Eosinophils / drug effects
  • Eosinophils / immunology*
  • Eosinophils / pathology
  • Forced Expiratory Volume
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Immunity, Innate
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-13 Receptor alpha1 Subunit / genetics
  • Interleukin-13 Receptor alpha1 Subunit / immunology
  • Interleukin-33
  • Interleukin-5 / genetics
  • Interleukin-5 / immunology
  • Interleukin-7 Receptor alpha Subunit / genetics
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Interleukins / genetics
  • Interleukins / immunology*
  • Male
  • Methacholine Chloride / pharmacology
  • Middle Aged
  • Primary Cell Culture
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / immunology
  • Sputum / cytology
  • Sputum / immunology

Substances

  • Allergens
  • CRLF2 protein, human
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Cytokines
  • IL1RL1 protein, human
  • IL33 protein, human
  • IL5 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • Interleukin-33
  • Interleukin-5
  • Interleukin-7 Receptor alpha Subunit
  • Interleukins
  • Receptors, Cell Surface
  • Receptors, Cytokine
  • interleukin-13, human
  • Methacholine Chloride
  • thymic stromal lymphopoietin