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* Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
CSF-1, the major regulator of macrophage (M
) 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 M accumulation, activation, and M-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 M 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 M 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 M to up-regulate CSF-1-dependent expression of IFN-
. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants 36149 and 52369 (to V.R.K.) and CA32551 (to E.R.S.), Albert Einstein College of Medicine Cancer Center Grant 5P30-CA13330, an American Society of Hematology Fellow Scholar Award (to X.-M.D.), and a Leukemia and Lymphoma Society Special Fellow Award (to X.-M.D.).
2 Address correspondence and reprint requests to Dr. Vicki R. Kelley, Brigham and Women’s Hospital, Harvard Institutes of Medicine, 4 Black Fan Circle, Boston, MA 02115. E-mail address: vkelley{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: M, macrophage; TEC, tubular epithelial cell; WT, wild type; UUO, unilateral ureteral obstruction; sgCSF-1, secreted glycoprotein CSF-1; spCSF-1, secreted proteoglycan CSF-1; csCSF-1, cell surface CSF-1; osteopetrotic, Csf1op/Csf1op; ChS, chondroitin sulfate; sppCSF-1, secreted proteoglycan precursor of CSF-1; sgpCSF-1, secreted glycoprotein precursor of CSF-1; TgCS, cell surface transgene; TgSPP, secreted proteoglycan precursor transgene; TgSGP, secreted glycoprotein precursor transgene; EGFP, enhanced GFP; CL, contralateral; 
-gal, 5-bromo-4-chloro-3-indolyl--D-galactopyranoside; LTL, lotus tetragonolobus lectin; DBA, dolichos biflorus aggulutinin; iNOS, inducible NO synthase; DC, dendritic cell.
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