title: Reduced macrophage recruitment, proliferation, and activation in colony-stimulating factor-1-deficient mice results in decreased tubular apoptosis during renal inflammation.
abstract: Kidney tubular epithelial cell (TEC) death may be dependent on the number and activation state of macrophages (M phi) during inflammation. Our prior studies indicate that activated M phi release soluble mediators that incite TEC death, and reducing intrarenal M phi during kidney disease diminishes TEC apoptosis. CSF-1 is required for M phi proliferation and survival. We hypothesized that in the absence of CSF-1, M phi-mediated TEC apoptosis would be prevented during renal inflammation. To test this hypothesis, we evaluated renal inflammation during unilateral ureter obstruction in CSF-1-deficient (Csf1(op)/Csf1(op)) mice. We detected fewer M phi and T cells and less apoptotic TEC in the obstructed kidneys of Csf1(op)/Csf1(op) mice compared with wild-type (WT) mice. The decrease in intrarenal M phi resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced M phi activation. There were far fewer activated (CD69, CD23, Ia, surface expression) M phi in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow M phi preincubated with anti-CSF-1 receptor Ab or anti-CSF-1 neutralizing Ab were resistant to LPS- and IFN-gamma-induced activation. We detected fewer apoptotic-inducing molecules (reactive oxygen species, TNF-alpha, inducible NO synthase) in 1) M phi propagated from obstructed Csf1(op)/Csf1(op) compared with WT kidneys, and 2) WT bone marrow M phi blocked with anti-CSF-1 receptor or anti-CSF-1 Ab compared with the isotype control. Furthermore, blocking CSF-1 or the CSF-1 receptor induced less TEC apoptosis than the isotype control. We suggest that during renal inflammation, CSF-1 mediates M phi recruitment, proliferation, activation, and, in turn, TEC apoptosis.
authors.affiliation: Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Lenda
authors.forename: Eriya
authors.initials: E
authors.lastname: Kikawada
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007682:Kidney Pelvis / Q000276:immunology / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology*; D008262:Macrophage Activation / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014517:Ureteral Obstruction / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018932:Chemokine CCL2; D016173:Macrophage Colony-Stimulating Factor