title: CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus.
abstract: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that can affect multiple end organs. Kidney and brain are two of the organs most commonly involved in SLE. Past studies have suggested the importance of macrophages in the pathogenesis of lupus nephritis (LN). Furthermore, as the immune effectors of the brain, microglia have been implicated in pathways leading to neuropsychiatric SLE (NPSLE). We depleted macrophages and microglia using GW2580, a small colony stimulating factor-1 receptor (CSF-1R) kinase inhibitor, in MRL-lpr/lpr (MRL/lpr) mice, a classic murine lupus model that displays features of both LN and NPSLE. Treatment was initiated before the onset of disease, and mice were followed for the development of LN and neurobehavioral dysfunction throughout the study. Treatment with GW2580 significantly ameliorated kidney disease, as evidenced by decreased proteinuria, BUN, and improved renal histopathology, despite equivalent levels of IgG and C3 deposition in the kidneys of treated and control mice. We were able to confirm macrophage depletion within the kidney via IBA-1 staining. Furthermore, we observed specific improvement in the depression-like behavioral deficit of MRL/lpr mice with GW2580 treatment. Circulating antibody and autoantibody levels were, however, not affected. These results provide additional support for the role of macrophages as a potentially valuable therapeutic target in SLE. Inhibiting CSF-1 receptor signaling would be more targeted than current immunosuppressive therapies, and may hold promise for the treatment of renal and neuropsychiatric end organ disease manifestations.
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, USA.
authors: Samantha A
authors: SA
authors: Chalmers
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, USA.
authors: Jing
authors: J
authors: Wen
authors: Montefiore Medical Center, Department of Medicine, Bronx, NY, USA.
authors: Justine
authors: J
authors: Shum
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, USA.
authors: Jessica
authors: J
authors: Doerner
authors: Cleveland Clinic, Department of Pathology, Cleveland, OH, USA.
authors: Leal
authors: L
authors: Herlitz
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, USA; Albert Einstein College of Medicine, Division of Rheumatology, Bronx, NY, USA. Electronic address: chaim.putterman@einstein.yu.edu.
authors: Chaim
authors: C
authors: Putterman
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology / Q000627:therapeutic use*; D000974:Antibodies, Antinuclear / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003863:Depression / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008124:Locomotion / Q000187:drug effects; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000523:psychology; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000523:psychology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D019463:Mice, Inbred MRL lpr; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D000974:Antibodies, Antinuclear; D002843:Chromatin; D016207:Cytokines; D007074:Immunoglobulin G; D011743:Pyrimidines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D003165:Complement System Proteins
keywords: CSF-1R; Lupus nephritis; Macrophages; Neuropsychiatric lupus; SLE