title: Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration.
abstract: BACKGROUND
  In anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV), persistent inflammation within the vessel wall suggests perturbed neutrophil trafficking leading to accumulation of activated neutrophils in the microvascular compartment. CXCR1 and CXCR2, being major chemokine receptors on neutrophils, are largely responsible for neutrophil recruitment. We speculate that down-regulated expression of CXCR1/2 retains neutrophils within the vessel wall and, consequently, leads to vessel damage.
  
  
  METHODS
  Membrane expression of CXCR1/2 on neutrophils was assessed by flow cytometry. Serum levels of interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), angiopoietin 1 and angiopoietin 2 from quiescent and active AAV patients and healthy controls (HC) were quantified by ELISA. Adhesion and transendothelial migration of isolated neutrophils were analyzed using adhesion assays and Transwell systems, respectively.
  
  
  RESULTS
  Expression of CXCR1 and CXCR2 on neutrophils was significantly decreased in AAV patients compared to HC. Levels of IL-8, which, as TNFα, dose-dependently down-regulated CXCR1 and CXCR2 expression on neutrophils in vitro, were significantly increased in the serum of patients with active AAV and correlated negatively with CXCR1/CXCR2 expression on neutrophils, even in quiescent patients. Blocking CXCR1 and CXCR2 with repertaxin increased neutrophil adhesion and inhibited migration through a glomerular endothelial cell layer.
  
  
  CONCLUSIONS
  Expression of CXCR1 and CXCR2 is decreased in AAV, potentially induced by circulating proinflammatory cytokines such as IL-8. Down-regulation of these chemokine receptors could increase neutrophil adhesion and impair its migration through the glomerular endothelium, contributing to neutrophil accumulation and, in concert with ANCA, persistent inflammation within the vessel wall.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, PO Box 30,001, 9700 RB, Groningen, The Netherlands.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Johanna
authors.initials: J
authors.lastname: Westra
authors.forename: Abraham
authors.initials: A
authors.lastname: Rutgers
authors.forename: Berber
authors.initials: B
authors.lastname: Doornbos-Van der Meer
authors.forename: Minke G
authors.initials: MG
authors.lastname: Huitema
authors.forename: Coen A
authors.initials: CA
authors.lastname: Stegeman
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000097:blood / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000276:immunology* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology; D014657:Vasculitis / Q000097:blood / Q000276:immunology* / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha