Distinct in vivo roles of colony-stimulating factor-1 isoforms in renal inflammation.
CSF-1, the major regulator of macrophage (Mphi) 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 Mphi accumulation, activation, and Mphi-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 Mphi 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 Mphi 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 Mphi to up-regulate CSF-1-dependent expression of IFN-gamma. 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.
Jang
Mei-Huei
MH
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Herber
Deborah M
DM
Jiang
Xinnong
X
Nandi
Sayan
S
Dai
Xu-Ming
XM
Zeller
Geraldine
G
Stanley
E Richard
ER
Kelley
Vicki R
VR
D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D011509:Proteoglycans / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014517:Ureteral Obstruction / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011509:Proteoglycans; D016173:Macrophage Colony-Stimulating Factor