Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation

Abstract

We recently reported evidence suggesting that migrating macrophages (Mws) eliminate renal crystals in hyperoxaluric mice. Mws can be inflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2Mw phenotype. M2Mws 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 M2Mws in renal crystal formation during hyperoxaluria using CSF-1-deficient mice, which lack M2Mws. 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 Mws showed that CSF-1 deficiency resulted in a smaller population of CD11b + F4/80 + CD163 + CD206 hi cells, which represent M2-like Mws. Additionally, transfusion of M2Mws 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 Mws than M1-polarized Mws 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.

Calcium Oxalate Stone Fragment and Crystal Phagocytosis by Human Macrophages

“…Gene array profiling studies of the kidneys of CSF-1 deficient hyperoxluric mice showed disordered expression of anti- inflammatory genes and increase in CaOx crystal deposition indicating a critical role for CSF-1 signaling. 27 …”

“…It was previously hypothesized, 9, 10, 27, 28 the kidney may actively remove interstitial crystal deposits through a cellular mechanism that includes a “sterile inflammation”. Our present and previous data suggest that enhanced production of certain cytokines/chemokines such as CCL2 by macrophages and epithelial cells in response to CaOx is an important part of such mechanism that involves several steps: a) recruitment of CCR2+ monocytes; b) in situ differentiation of recruited blood monocytes into “healing” anti-inflammatory macrophages and c) subsequent macrophage-mediated clearance of CaOx deposits.…”

Urinary metabonomics elucidate the therapeutic mechanism of Orthosiphon stamineus in mouse crystal-induced kidney injury

“…In this study, we established the glyoxylate-induced crystal related kidney injury model following the method described previously (Okada et al, 2007, Taguchi et al, 2014. Then, we applied this model to investigate the protective effect and mechanism of OS using a metabonomics-based approach.…”

Novel Insights into Crystal-Induced Kidney Injury

“…They are thought to contribute to the removal of crystal deposits via phagocytosis and digestion [1]. Consistently, colony-stimulating factor suppressed renal crystal deposition by inducing M2 macrophages in the kidneys of hyperoxaluric mice [43]. However, the molecular mechanisms that trigger the formation of crystal granulomas in crystalline CKD are unknown to date.…”