Open Access Research article

Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration

Nan Hu1, Johanna Westra1, Abraham Rutgers1, Berber Doornbos-Van der Meer1, Minke G Huitema1, Coen A Stegeman2, Wayel H Abdulahad1, Simon C Satchell4, Peter W Mathieson4, Peter Heeringa3 and Cees G M Kallenberg1*

Author Affiliations

1 Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands

2 Department of Nephrology, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands

3 Department of Pathology and Medical Biology, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands

4 Academic Renal Unit, University of Bristol, Second Floor, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK

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Arthritis Research & Therapy 2011, 13:R201  doi:10.1186/ar3534

Published: 8 December 2011

Abstract

Introduction

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.