title: CX3CR1 reduces kidney fibrosis by inhibiting local proliferation of profibrotic macrophages.
abstract: A dense network of macrophages and dendritic cells (DC) expressing the chemokine receptor CX3CR1 populates most tissues. We recently reported that CX3CR1 regulates the abundance of CD11c(+) DC in the kidney and thereby promotes renal inflammation in glomerulonephritis. Given that chronic inflammation usually causes fibrosis, we hypothesized that CX3CR1 deficiency should attenuate renal fibrosis. However, when we tested this hypothesis using the DC-independent murine fibrosis model of unilateral ureteral obstruction, kidney fibrosis was unexpectedly more severe, despite less intrarenal inflammation. Two-photon imaging and flow cytometry revealed in kidneys of CX3CR1-deficient mice more motile Ly6C/Gr-1(+) macrophages. Flow cytometry verified that renal macrophages were more abundant in the absence of CX3CR1 and produced more of the key profibrotic mediator, TGF-β. Macrophages accumulated because of higher intrarenal proliferation, despite reduced monocyte recruitment and higher signs of apoptosis within the kidney. These findings support the theory that tissue macrophage numbers are regulated through local proliferation and identify CX3CR1 as a regulator of such proliferation. Thus, CX3CR1 inhibition should be avoided in DC-independent inflammatory diseases because it may promote fibrosis.
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms University, 53105 Bonn, Germany; Institute for Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, 45147 Essen, Germany;
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Engel
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms University, 53105 Bonn, Germany;
authors.forename: Torsten A
authors.initials: TA
authors.lastname: Krause
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Snelgrove
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms University, 53105 Bonn, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thiebes
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.affiliation: Institute of Pathology, Rheinisch-Westfälische Technische Hochschule, 52074 Aachen, Germany; and Department of Nephrology, Rheinisch-Westfälische Technische Hochschule, 52074 Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria 3168, Australia;
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms University, 53105 Bonn, Germany; ckurts@web.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine