Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice.
Inflammation in the kidney and other tissues (lung, and salivary and lacrimal glands) is characteristic of MRL-Fas(lpr) mice with features of lupus. Macrophages (Mphi) are prominent in these tissues. Given that 1) Mphi survival, recruitment, proliferation, and activation during inflammation is dependent on CSF-1, 2) Mphi mediate renal resident cell apoptosis, and 3) CSF-1 is up-regulated in MRL-Fas(lpr) mice before, and during nephritis, we hypothesized that CSF-1-deficient MRL-Fas(lpr) mice would be protected from Mphi-mediated nephritis, and the systemic illness. To test this hypothesis, we compared CSF-1-deficient MRL-Fas(lpr) with wild-type strains. Renal pathology is suppressed and function improved in CSF-1-deficient MRL-Fas(lpr) mice. There are far fewer intrarenal Mphi and T cells in CSF-1-deficient MRL-Fas(lpr) vs wild-type kidneys. This leukocytic reduction results from suppressed infiltration, and intrarenal proliferation, but not enhanced apoptosis. The CSF-1-deficient MRL-Fas(lpr) kidneys remain preserved as indicated by greatly reduced indices of injury (nephritogenic cytokines, tubular apoptosis, and proliferation). The renal protective mechanism in CSF-1-deficient mice is not limited to reduced intrarenal leukocytes; circulating Igs and autoantibodies, and renal Ig deposits are decreased. This may result from enhanced B cell apoptosis and fewer B cells in CSF-1-deficient MRL-Fas(lpr) mice. Furthermore, the systemic illness including, skin, lung, and lacrimal and salivary glands pathology, lymphadenopathy, and splenomegaly are dramatically suppressed in CSF-1-deficient MRL-Fas(lpr) as compared with wild-type mice. These results indicate that CSF-1 is an attractive therapeutic target to combat Mphi-, T cell-, and B cell-mediated autoimmune lupus.
Lenda
Deborah M
DM
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
Stanley
E Richard
ER
Kelley
Vicki R
VR
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002464:Cell Migration Inhibition; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology; D007765:Lacrimal Apparatus / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D007970:Leukopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D012867:Skin / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D018925:Chemokines; D003176:Complement C3; D016207:Cytokines; D006131:Growth Inhibitors; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D016173:Macrophage Colony-Stimulating Factor