CX3CR1 reduces kidney fibrosis by inhibiting local proliferation of profibrotic macrophages

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 inflammatio...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2015-02, Vol.194 (4), p.1628-1638
Main Authors: Engel, Daniel R, Krause, Torsten A, Snelgrove, Sarah L, Thiebes, Stephanie, Hickey, Michael J, Boor, Peter, Kitching, A Richard, Kurts, Christian
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
CX3C Chemokine Receptor 1
Disease Models, Animal
Fibrosis - metabolism
Fibrosis - pathology
Flow Cytometry
Immunohistochemistry
Kidney - immunology
Kidney - metabolism
Kidney - pathology
Macrophages - immunology
Macrophages - metabolism
Macrophages - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Real-Time Polymerase Chain Reaction
Receptors, Chemokine - immunology
Receptors, Chemokine - metabolism
Reverse Transcriptase Polymerase Chain Reaction
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1402149