Authors: van der Veen, B. S.¹; Petersen, A. H.¹; Belperio, J. A.²; Satchell, S. C.³; Mathieson, P. W.³; Molema, G.¹; Heeringa, P.

Source: Clinical & Experimental Immunology, Volume 158, Number 1, October 2009 , pp. 143-153(11)

Publisher: Wiley-Blackwell

Abstract:

Summary

Myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing crescentic glomerulonephritis (NCGN) is characterized by abundant leucocyte infiltration. Chemokines are chemotactic cytokines involved in receptor-mediated recruitment of leucocytes. Our objective was to analyse spatiotemporal gene expression of chemokines and chemokine receptors in anti-MPO-mediated NCGN, to find potential targets for intervening with leucocyte influx. NCGN was induced in mice by co-administration of anti-MPO immunoglobulin (Ig)G and lipopolysaccharide. mRNA expression levels of chemokines and chemokine receptors were analysed in whole kidney lysates as well as in laser microdissected glomeruli and tubulo-interstitial tissue 1 and 7 day(s) after NCGN induction. Several chemokines and chemokine receptors were induced or up-regulated in anti-MPO-mediated NCGN, both on day 1 (chemokines CCL3, 5; CXCL2, 5, 13; receptor CXCR2) and on day 7 (chemokines CCL2, 5, 7, 8, 17, 20; CXCL1, 2, 5, 10; CX₃CL1; receptors CCR2, 8; CX₃CR1). The expression levels of most chemokines and receptors were higher in glomeruli than in the tubulo-interstitium. Because of the temporal induction of CXCR2 on day 1, we hypothesized CXCR2 as a potential target for treatment in anti-MPO-induced NCGN. Inhibition of CXCR2 using a goat-anti-CXCR2 serum prior to NCGN induction increased glomerular neutrophil influx but did not affect crescent formation and albuminuria. In conclusion, expression levels of various chemokines and chemokine receptors were increased in anti-MPO NCGN, and expressed particularly in glomeruli. These chemokines and receptors may serve as potential targets for treatment. Inhibition of a single target, CXCR2, did not attenuate anti-MPO NCGN. Combinatorial interventions may be necessary to avoid redundancy.

Keywords: ANCA; chemokines; crescentic glomerulonephritis; CXCR2; MPO

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2249.2009.03993.x

Affiliations: 1: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, 2: Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, and 3: Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, UK

Publication date: 2009-10-01

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