title: Distinct roles of CSF-1 isoforms in lupus nephritis.
abstract: Colony-stimulating factor-1 (CSF-1), the principal growth factor for macrophages, is increased in the kidney, serum, and urine of patients with lupus nephritis, and eliminating CSF-1 suppresses lupus in MRL-Fas(lpr) mice. CSF-1 has three biologically active isoforms: a membrane-spanning cell surface glycoprotein (csCSF-1), a secreted proteoglycan (spCSF-1), and a secreted glycoprotein (sgCSF-1); the role of each isoform in the circulation and kidney in autoimmune disease is not well understood. Here, we constructed mutant MRL-Fas(lpr) mice that only express csCSF-1 or precursors of the spCSF-1 and sgCSF-1 isoforms. Both csCSF-1 and spCSF-1 shifted monocytes toward proinflammatory, activated populations, enhancing their recruitment into the kidney during lupus nephritis. With advancing lupus nephritis, spCSF-1 was the predominant isoform responsible for increasing circulating CSF-1 and, along with the csCSF-1 isoform, for increasing intrarenal CSF-1. Thus, csCSF-1 appears to initiate and promote the local activation of macrophages within the kidney. Intrarenal expression of csCSF-1 and spCSF-1 increases with advancing nephritis, thereby promoting the intrarenal recruitment of monocytes and expansion of Ly6C(hi) macrophages, which induce apoptosis of the renal parenchyma. Taken together, these data suggest that the three CSF-1 isoforms have distinct biologic properties, suggesting that blocking both circulating and intrarenal CSF-1 may be necessary for therapeutic efficacy.
authors: Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Julia
authors: J
authors: Menke
authors: Yasunori
authors: Y
authors: Iwata
authors: Whitney A
authors: WA
authors: Rabacal
authors: Ranu
authors: R
authors: Basu
authors: E Richard
authors: ER
authors: Stanley
authors: Vicki R
authors: VR
authors: Kelley
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D007668:Kidney / Q000378:metabolism*; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D020033:Protein Isoforms; D016173:Macrophage Colony-Stimulating Factor