Correspondence: Dr. Ulf Panzer, Third Medical Clinic, Hamburg-Eppendorf University Hospital, Martinistrasse 52, 20246 Hamburg, Germany. Email: ed.grubmah-inu.eku@reznap

E.M.D. and C.F.K. contributed equally to this work.

Received 2013 Oct 10; Accepted 2014 Apr 4.

Abstract

Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in T_H17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic T_H17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in T_H17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.

Keywords: GN, immunology, neutrophils, IL-17, chemokines, CXCL5

Abstract

Neutrophils are the most abundant type of leukocytes in the blood and form an indispensable part of the innate immune system. Their trafficking into peripheral tissues is pivotal in the defense against invading bacterial and fungal pathogens.¹ To ensure that neutrophils reach the sites of tissue injury, their recruitment is regulated by the local expression of chemoattractants, including chemokines. However, the infiltration of neutrophils also significantly contributes to end-organ damage in autoimmune diseases mediated by T helper (T_H) cell T_H17,² including human and experimental crescentic GN.³,⁴

Chemokines are a large family of small (8–12 kD) secreted proteins that are identified as attractants of different types of leukocytes, including neutrophils, to sites of infection and inflammation.⁵ They are produced locally in tissues and act through interaction with specific G protein–coupled receptors that are predominantly expressed on leukocytes. Neutrophil infiltration is mainly mediated by chemokines that have a glutamate-leucine-arginine motif (ELR^{chemokines). In humans, there are seven ELR chemokine ligands with a C-X-C motif (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8). Their chemotactic effects are mediated}via binding to the chemokine receptors CXCR1 and CXCR2. Mice lack complete homologs of the seven human ELR chemokines and have only five members (CXCL1, CXCL2, CXCL3, CXCL5, and CXCL7, which all bind to the murine CXCR2).⁶ Interestingly, previous reports show that IL-17A, the master effector cytokine of T_H17 cells, induces the expression of the ELR^{chemokines CXCL1, CXCL2, and CXCL5}⁷,⁸ and thereby might drive the recruitment of pathogenic neutrophils in autoimmunity. The development of a therapeutic strategy targeting ELR^{neutrophil–attracting chemokines or their receptors is complicated by an often overlapping expression pattern and function of these molecules in pathogen- and autoimmune-induced inflammatory reactions.}⁹

Here we describe for the first time a nonredundant function of the chemokines CXCL1 and CXCL5 in murine models of crescentic GN and acute bacterial pyelonephritis. CXCL1 mediated early glomerular neutrophil recruitment in the non-T cell–dependent initiation phase of GN, whereas CXCL5 was responsible for the infiltration of pathogenic neutrophils into sites of inflammation in later T_H17-dependent phases of the disease. Of note, CXCL5 did not affect neutrophil infiltration and bacterial clearance in a murine model of acute bacterial pyelonephritis, one of the most prevalent kidney infections in humans. These findings suggest that CXCL5 has a unique function in the trafficking of neutrophils in T_H17 cell–mediated autoimmunity, but not in the innate immune response. CXCL5 therefore represents an attractive therapeutic target for the restriction of pathogenic neutrophil infiltration in T_H17-driven autoimmune diseases without affecting the vital functions of neutrophils in the defense against acute bacterial infections.

Clinical characteristics of patients with acute ANCA-associated GN (patients 1–8) and acute pyelonephritis (patients 9–14) at the time of renal biopsy. pANCA, perinuclear ANCA; cANCA, cytoplasmic ANCA; PR3, proteinase 3; MPO, myeloperoxidase; CyP, cypionate.

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Acknowledgments

This study was supported by grants from the German Research Foundation (KFO 228: PA 754/7-2 to U.P. and C.F.K.; MI 476/4-2 to H.-W.M.).

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2013101061/-/DCSupplemental.

Footnotes

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