CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

Samantha A. Chalmers, Jing Wen, Justine Shum, Jessica Doerner, Leal Herlitz, Chaim Putterman

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
JournalClinical Immunology
DOIs
StateAccepted/In press - Jun 2 2016

Fingerprint

Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor
Lupus Nephritis
Kidney
Macrophages
Inbred MRL lpr Mouse
Systemic Lupus Erythematosus
Microglia
Central Nervous System Lupus Vasculitis
Macrophage Colony-Stimulating Factor Receptors
Blood Urea Nitrogen
Brain
Kidney Diseases
Immunosuppressive Agents
Proteinuria
Autoantibodies
Autoimmune Diseases
Phosphotransferases
Immunoglobulin G
Staining and Labeling

Keywords

  • CSF-1R
  • Lupus nephritis
  • Macrophages
  • Neuropsychiatric lupus
  • SLE

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. / Chalmers, Samantha A.; Wen, Jing; Shum, Justine; Doerner, Jessica; Herlitz, Leal; Putterman, Chaim.

In: Clinical Immunology, 02.06.2016.

Research output: Contribution to journalArticle

Chalmers, Samantha A. ; Wen, Jing ; Shum, Justine ; Doerner, Jessica ; Herlitz, Leal ; Putterman, Chaim. / CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. In: Clinical Immunology. 2016.
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