Epstein-Barr virus-induced gene 2 mediates allergen-induced leukocyte migration into airways

Zhong Jian Shen, Jie Hu, Venkatesh P. Kashi, Elizabeth A. Kelly, Loren C. Denlinger, Kevan Lutchman, Jeffrey G. McDonald, Nizar N. Jarjour, James S. Malter

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Rationale: Leukocyte recruitment to sites of allergic inflammation depends on the local production of priming cytokines, chemokines, and potentially other mediators. Previously, we showed that eosinophils (Eos) express numerous orphan G-protein-coupled receptors, including Epstein-Barr virus-induced gene 2 (EBI2). Despite its contribution to inflammatory diseases, the role of EBI2 in pulmonary eosinophilia is unknown. Objectives: To determine whether oxysterol ligands for EBI2 are increased in asthma exacerbation, and if or how they promote Eos pulmonary migration. Methods: EBI2 ligands and pulmonary eosinophilia were measured in the bronchoalveolar lavage fluid from patients with mild asthma 48 hours after acute allergen challenge. In vitro, the ability of EBI2 ligands alone or in combination with IL-5 priming to induce the migration of human blood Eos was assessed. Measurements and Main Results: EBI2 was constitutively and stably expressed in peripheral blood Eos. Eos treated with the EBI2 ligands showed significantly increased transwell migration that was enhanced by priming with physiologic doses of IL-5. Migration was suppressed by inhibitors of the prolyl isomerase Pin1 or extracellular signal-regulated kinases (ERK) 1/2 or by pertussis toxin. EBI2 signaling activated Pin1 isomerase activity through a cascade that was sensitive to ERK inhibitors and pertussis toxin. The concentration of EBI2 ligands was significantly increased in the bronchoalveolar lavage fluid 48 hours after segmental allergen challenge and strongly correlated with the increased numbers of Eos, lymphocytes, and neutrophils in the airways. Conclusions: Oxysterols are increased in inflamed airways after allergen challenge and, through G-protein subunit a, ERK, and Pin1 signaling, likely participate in the regulation of Eos migration into the lung in people with asthma.

Original languageEnglish (US)
Pages (from-to)1576-1585
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume195
Issue number12
DOIs
StatePublished - Jun 15 2017

Fingerprint

Human Herpesvirus 4
Allergens
Leukocytes
Eosinophils
Genes
Ligands
Pulmonary Eosinophilia
Asthma
Interleukin-5
Extracellular Signal-Regulated MAP Kinases
Pertussis Toxin
Bronchoalveolar Lavage Fluid
Peptidylprolyl Isomerase
Isomerases
Lung
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Protein Subunits
Lymphocyte Count
G-Protein-Coupled Receptors

Keywords

  • Asthma
  • EBI2
  • Eosinophils
  • Migration
  • Pin1

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Epstein-Barr virus-induced gene 2 mediates allergen-induced leukocyte migration into airways. / Shen, Zhong Jian; Hu, Jie; Kashi, Venkatesh P.; Kelly, Elizabeth A.; Denlinger, Loren C.; Lutchman, Kevan; McDonald, Jeffrey G.; Jarjour, Nizar N.; Malter, James S.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 195, No. 12, 15.06.2017, p. 1576-1585.

Research output: Contribution to journalArticle

Shen, Zhong Jian ; Hu, Jie ; Kashi, Venkatesh P. ; Kelly, Elizabeth A. ; Denlinger, Loren C. ; Lutchman, Kevan ; McDonald, Jeffrey G. ; Jarjour, Nizar N. ; Malter, James S. / Epstein-Barr virus-induced gene 2 mediates allergen-induced leukocyte migration into airways. In: American Journal of Respiratory and Critical Care Medicine. 2017 ; Vol. 195, No. 12. pp. 1576-1585.
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AU - Kelly, Elizabeth A.

AU - Denlinger, Loren C.

AU - Lutchman, Kevan

AU - McDonald, Jeffrey G.

AU - Jarjour, Nizar N.

AU - Malter, James S.

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AB - Rationale: Leukocyte recruitment to sites of allergic inflammation depends on the local production of priming cytokines, chemokines, and potentially other mediators. Previously, we showed that eosinophils (Eos) express numerous orphan G-protein-coupled receptors, including Epstein-Barr virus-induced gene 2 (EBI2). Despite its contribution to inflammatory diseases, the role of EBI2 in pulmonary eosinophilia is unknown. Objectives: To determine whether oxysterol ligands for EBI2 are increased in asthma exacerbation, and if or how they promote Eos pulmonary migration. Methods: EBI2 ligands and pulmonary eosinophilia were measured in the bronchoalveolar lavage fluid from patients with mild asthma 48 hours after acute allergen challenge. In vitro, the ability of EBI2 ligands alone or in combination with IL-5 priming to induce the migration of human blood Eos was assessed. Measurements and Main Results: EBI2 was constitutively and stably expressed in peripheral blood Eos. Eos treated with the EBI2 ligands showed significantly increased transwell migration that was enhanced by priming with physiologic doses of IL-5. Migration was suppressed by inhibitors of the prolyl isomerase Pin1 or extracellular signal-regulated kinases (ERK) 1/2 or by pertussis toxin. EBI2 signaling activated Pin1 isomerase activity through a cascade that was sensitive to ERK inhibitors and pertussis toxin. The concentration of EBI2 ligands was significantly increased in the bronchoalveolar lavage fluid 48 hours after segmental allergen challenge and strongly correlated with the increased numbers of Eos, lymphocytes, and neutrophils in the airways. Conclusions: Oxysterols are increased in inflamed airways after allergen challenge and, through G-protein subunit a, ERK, and Pin1 signaling, likely participate in the regulation of Eos migration into the lung in people with asthma.

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