Macrophage depletion ameliorates nephritis induced by pathogenic antibodies

Abstract

Objective Kidney involvement affects 40–60% of patients with lupus and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, “off target” effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. Methods In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. Results We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, or serum urea seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with LN. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Conclusions Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.

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

“…We have confirmed the ability of GW2580 to deplete both macrophages [17] and microglia (unpublished data). Specifically, we described the effect of GW2580 on kidney and splenic macrophages, as well as on circulating monocytes [17].…”

“…who was blinded to the treatment groups. The scoring system used has been described previously [17]. Briefly, the sections were assigned a score of 0-4 (where 0 is no disease, and 4 is severe disease) within different categories that pertained to glomerular or tubular pathology (glomerular deposits, endocapillary proliferation, glomerular crescent formation, interstitial inflammation, and tubular casts and dilatation).…”

“…Thus, evidence that macrophages and microglia are important to the pathogenesis of LN and NPSLE, respectively, needs to be further investigated. We previously had demonstrated the importance of macrophages in the pathogenesis of nephritis in an inducible mouse model of antibody mediated kidney disease known as nephrotoxic serum nephritis (NTN), which models LN [17]. In this study, we sought to expand upon these studies by assessing the effect of macrophage depletion in a spontaneous (and more severe) model of SLE known as the MRL/lpr mouse.…”

Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus

“…Renal macrophages from lupus-prone mice exhibit different structure and function from normal mice [2]. Moreover, macrophage depletion could ameliorate lupus nephritis in mice [3], suggesting a key role of macrophages in SLE.…”

Biomarkers for Kidney Involvement in Pediatric Lupus

“…This intervention led to the amelioration of LN and improved renal function, reduction in proteinuria and lower expression levels of inflammatory cytokines [104]. …”