Colony-stimulating factor-1 signaling suppresses renal crystal formation

J Am Soc Nephrol. 2014 Aug;25(8):1680-97. doi: 10.1681/ASN.2013060675. Epub 2014 Feb 27.

Abstract

We recently reported evidence suggesting that migrating macrophages (Mϕs) eliminate renal crystals in hyperoxaluric mice. Mϕs can be inflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2Mϕ phenotype. M2Mϕs promote renal tissue repair and regeneration, but it is not clear whether these cells are involved in suppressing renal crystal formation. We investigated the role of M2Mϕs in renal crystal formation during hyperoxaluria using CSF-1-deficient mice, which lack M2Mϕs. Compared with wild-type mice, CSF-1-deficient mice had significantly higher amounts of renal calcium oxalate crystal deposition. Treatment with recombinant human CSF-1 increased the expression of M2-related genes and markedly decreased the number of renal crystals in both CSF-1-deficient and wild-type mice. Flow cytometry of sorted renal Mϕs showed that CSF-1 deficiency resulted in a smaller population of CD11b(+)F4/80(+)CD163(+)CD206(hi) cells, which represent M2-like Mϕs. Additionally, transfusion of M2Mϕs into CSF-1-deficient mice suppressed renal crystal deposition. In vitro phagocytosis assays with calcium oxalate monohydrate crystals showed a higher rate of crystal phagocytosis by M2-polarized Mϕs than M1-polarized Mϕs or renal tubular cells. Gene array profiling showed that CSF-1 deficiency resulted in disordered M2- and stone-related gene expressions. Collectively, our results provide compelling evidence for a suppressive role of CSF-1 signaling in renal crystal formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / genetics
  • Annexin A2 / metabolism
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Calcium Oxalate / metabolism
  • Cell Culture Techniques
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Hyperoxaluria / etiology
  • Hyperoxaluria / metabolism
  • Hyperoxaluria / pathology*
  • Kidney Calculi / etiology
  • Kidney Calculi / metabolism
  • Kidney Calculi / pathology*
  • Macrophage Colony-Stimulating Factor / physiology*
  • Macrophages / physiology*
  • Male
  • Mice
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Phagocytosis / physiology
  • RNA, Messenger / metabolism
  • Recombinant Proteins
  • Signal Transduction / physiology*

Substances

  • Annexin A2
  • Antigens, Differentiation
  • Chemokine CCL2
  • Hyaluronan Receptors
  • RNA, Messenger
  • Recombinant Proteins
  • monocyte-macrophage differentiation antigen
  • Osteopontin
  • Calcium Oxalate
  • Macrophage Colony-Stimulating Factor