Distinct In Vivo Roles of Colony-Stimulating Factor-1 Isoforms in Renal Inflammation

Abstract

CSF-1, the major regulator of macrophage (Mφ) development, has three biologically active isoforms: a membrane-spanning, cell surface glycoprotein, a secreted glycoprotein, and a secreted proteoglycan. We hypothesized that there are shared and unique roles of individual CSF-1 isoforms during renal inflammation. To test this, we evaluated transgenic mice only expressing the cell surface or precursors of the secreted CSF-1 isoforms for Mφ accumulation, activation, and Mφ-mediated tubular epithelial cell (TEC) apoptosis during unilateral ureteral obstruction. The only difference between secreted proteoglycan and secreted glycoprotein CSF-1 isoforms is the presence (proteoglycan) or absence (glycoprotein) of an 18-kDa chondroitin sulfate glycosaminoglycan. We report that 1) cell surface CSF-1 isoform is sufficient to restore Mφ accumulation, activation, and TEC apoptosis to wild-type levels and is substantially more effective than the secreted CSF-1 isoforms; 2) the chondroitin sulfate glycosaminoglycan facilitates Mφ accumulation, activation, and TEC apoptosis; 3) increasing the level of secreted proteoglycan CSF-1 in serum amplifies renal inflammation; and 4) cell-cell contact is required for Mφ to up-regulate CSF-1-dependent expression of IFN-γ. Taken together, we have identified central roles for the cell surface CSF-1 and the chondroitin sulfate chain on secreted proteoglycan CSF-1 during renal inflammation.

Circulating CSF-1 Promotes Monocyte and Macrophage Phenotypes that Enhance Lupus Nephritis

“…The MRL-Fas lpr kidney may be self-destructive. Because renal TECs are a rich source of CSF-1 during inflammation, 20 CSF-1 originating from the kidney may, in part, account for the rise in circulating CSF-1 that drives Mø Figure 7. CSF-1 is elevated in urine and serum of patients with lupus nephritis and correlates with disease activity.…”

“…41 To identify ␤-galactosidase encoded by lacZ (CSF-1 expression), we treated frozen kidney sections as described previously. 20 …”

“…[17][18][19] Intrarenal CSF-1 expression occurs during inflammation and expression is largely limited to tubular epithelial cells (TECs). 20 Moreover, the rise in circulating CSF-1 precedes intrarenal CSF-1 expression and is bimodal in MRL-Fas lpr mice. CSF-1 is upregulated in neonates, declines to normal levels, and then progressively rises with advancing kidney disease in MRL-Fas lpr mice.…”

Dendritic Cells in the Kidney

“…It is interesting that engagement of the CSF-1 receptor is required for the differentiation and survival of myeloid DC, 44 and constitutive expression of CSF-1 (i.e., M-CSF, a major chemoattractant and growth factor for mononuclear phagocytes 45 ) by renal epithelial cells seems to be more prominent in the medulla than in the cortex at steady state. 46,47 Whether this alone explains the heterogeneity of rDC is unclear. More likely, other differentially expressed trophic ligands (thymic stromal lymphopoietin-like factors that may be elaborated by renal epithelial cells or interstitial stromal cell populations 48,49 ) and extracellular matrices within the kidney also contribute to the specification of rDC.…”

Distinct Roles of CSF-1 Isoforms in Lupus Nephritis

“…Our previous studies indicated that the individual csCSF-1 and the spCSF-1 and sgCSF-1 isoforms have distinct functions in nonautoimmune incited renal inflammation on the basis of stability, availability, and the large (approximately 18,000 M r ) chondroitin sulfate chain (ChS) on spCSF-1, but not sgCSF-1. 13 To design a CSF-1 targeted therapeutic approach for lupus nephritis, it is essential to decipher whether blocking CSF-1 expression in the circulation and/or Figure 1. spCSF-1, but not csCSF-1, contributes to the increase in serum CSF-1, and both are upregulated in the kidney with advancing disease in MRL-Fas lpr mice.…”