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Negative Role of Colony-Stimulating Factor-1 in Macrophage, T Cell, and B Cell Mediated Autoimmune Disease in MRL-Fas^lpr Mice¹

Deborah M. Lenda^*, E. Richard Stanley and Vicki R. Kelley^2,*

^* Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Harvard University Medical School, Boston, MA 02115; and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461

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 (M) are prominent in these tissues. Given that 1) M survival, recruitment, proliferation, and activation during inflammation is dependent on CSF-1, 2) M 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 M-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 M 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 M-, T cell-, and B cell-mediated autoimmune lupus.

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