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.