Analysis of Renal Mononuclear Phagocytes in Murine Models of SLE

Abstract

In this chapter we present methods for the isolation and characterization of mononuclear phagocytes from the kidneys of mice with SLE. Activation of these cells is associated with the onset of clinical disease in mice and infiltration with these cells is associated with poor prognosis in humans. Using magnetic beads followed by flow cytometric sorting, pure populations of cells are obtained that are functional in a variety of assays. Sufficient numbers of cells are obtained for genomic characterization. An analysis of the function of these cells should lead to a better understanding of the inflammatory processes that cause renal impairment in SLE and other renal inflammatory diseases.

Macrophage depletion ameliorates nephritis induced by pathogenic antibodies

“…Studies by Davidson et al [1, 7] described distinct macrophage populations present within murine LN kidneys. These studies, while suggestive, do not necessarily distinguish whether macrophages are the primary cause of disease, or whether macrophage infiltration is a secondary phenomenon.…”

“…Even with current immunosuppressive regimens, chronic renal insufficiency develops in about a quarter of patients. In a two year follow up of patients with LN, the complete remission rate with current treatment regimens was less than 50%, and the relapse rate was as high as 30% [1]. A better understanding of disease pathogenesis could lead to the discovery of more targeted therapies, which may prevent or suppress relapses and improve long term kidney prognosis.…”

“…In human lupus, renal mononuclear phagocyte infiltration is associated with poor outcomes [6]. Furthermore, studies have shown that unique, activated populations of macrophages are present during active murine LN [1, 7, 8]. Additionally, depletion studies have sought to demonstrate that macrophages are not just present during disease, but also actively contribute to pathogenesis.…”

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

“…In both LN patients and mouse models of SLE, elevated levels of CSF-1 are found in the serum, urine, and kidneys, with urine and serum levels correlating with LN disease activity [8-11]. An influx of macrophages with a unique activated phenotype can be seen in both murine [12, 13] and human LN [14, 15], with macrophages accumulating both periglomerularly and intraglomerularly [16-18]. However, while the presence of macrophages within kidneys displaying active LN is consistent with a role of macrophages in disease pathogenesis, it does not prove that they are necessary to cause disease.…”

Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton’s Tyrosine Kinase

“…Current therapies for lupus nephritis (LN) consist mainly of non-specific immunosuppression which can be associated with dangerous side effects, yet often fail at producing long term remission. Further research efforts into the pathogenesis of LN and new therapeutic targets are necessary to improve patient care and the long term prognosis 2 .…”