title: Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis.
abstract: Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas(lpr)) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas(lpr) mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas(lpr) mice. Using mutant MRL-Fas(lpr) strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC(low)CD11b(+)), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC(low)CD11b(+)Ly6C(high)) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b(+)CSF-1R(+) or CD68(+)) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.
authors.affiliation: Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Menke
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Rabacal
authors.forename: Katelyn T
authors.initials: KT
authors.lastname: Byrne
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iwata
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Schwartz
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwarting
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008181:Lupus Nephritis / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood* / Q000235:genetics / Q000502:physiology / Q000652:urine; D008264:Macrophages / Q000145:classification / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D009000:Monocytes / Q000145:classification / Q000473:pathology / Q000502:physiology*; D010641:Phenotype
chemical_list: D016173:Macrophage Colony-Stimulating Factor