CX3CR1 reduces kidney fibrosis by inhibiting local proliferation of profibrotic macrophages

J Immunol. 2015 Feb 15;194(4):1628-38. doi: 10.4049/jimmunol.1402149. Epub 2015 Jan 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Proliferation*
  • 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


  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Receptors, Chemokine