Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation

We recently reported evidence suggesting that migrating macrophages (M phi s) eliminate renal crystals in hyperoxaluric mice. M phi s can be inflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2M phi phenotype. M2M phi s 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 M2M phi s in renal crystal formation during hyperoxaluria using CSF-1-deficient mice, which lack M2M phi s. 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 M phi s showed that CSF-1 deficiency resulted in a smaller population of CD11b(+)F4/80(+)CD163(+)CD206(hi) cells, which represent M2-like M phi s. Additionally, transfusion of M2M phi s 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 M phi s than M1-polarized M phi s 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.