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  • CDK4 inhibitor Targeting a specific cell type rather


    Targeting a specific cell type, rather than the broad cytotoxicity exhibited by some of the pharmacological agents currently used to treat lupus, may improve efficacy and decrease off target toxicity. 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. The MRL/lpr strain is a classic, validated model for the severe crescentic glomerulonephritis seen in LN patients, as well as for NPSLE, as the mice exhibit depression-like behavior and cognitive deficits [21], [22]. We utilized an orally administered kinase inhibitor specific for the CSF-1R kinase, known as GW2580, to inhibit CSF-1R signaling. We assessed treatment with GW2580 in MRL/lpr mice, and evaluated its effects on CDK4 inhibitor and kidney disease.
    Materials and methods
    Discussion GW2580 is a kinase inhibitor specific for CSF-1R [30], a receptor important for macrophage and microglia function and survival. We have confirmed the ability of GW2580 to deplete both macrophages [17] and microglia (unpublished data).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]. Furthermore, additional studies confirmed the ability of GW2580 to systemically deplete macrophages, including in organs such as the liver [30], [31]. We were able to use this drug to target macrophages and microglia before the onset of disease in the MRL/lpr strain, a mouse model validated for the study of SLE, including LN and NPSLE. Prophylactic treatment with GW2580 ameliorated kidney disease, as assessed by decreased proteinuria, improved BUN levels, and improved renal histopathology. Moreover, GW2580 treatment improved depression-like behavior. Macrophages have been previously studied in the context of LN [5], [32]. Activated macrophages not seen in healthy kidneys are found in active LN, both in murine models and human disease [12], [14], [15]. Additionally, CSF-1 is a validated biomarker for LN disease activity, in both the serum and urine [9]. Past studies have looked at targeting the CSF-1/CSF-1R signaling pathway in the MRL/lpr model. Congenital deletion (knockout) of either of these interacting molecules protected MRL/lpr mice from the development of severe nephritis; however, because macrophages play an important role in development, knockout mice suffered developmental defects including compromised bone marrow compartments, confounding interpretation of the study [11]. We previously showed the importance of macrophages in an inducible model of LN [17]. Depleting macrophages prophylactically with GW2580 ameliorated kidney damage and improved renal function. Furthermore, we found that GW2580 given after the onset of disease in the NTN model could still provide protective benefits – highlighting the therapeutic potential of targeting macrophages. Our present study examined the effects of depleting macrophages in a spontaneous model of LN, while also circumventing any developmental defects by avoiding genetic manipulation. Although the mice were sacrificed before the control mice reached extremely high levels of proteinuria, we believe the results still indicate the promising potential of this drug in the context of LN. Although serum GW2580 levels were not measured, we have effectively used this dose of GW2580 in previous experiments, and we confirmed the efficacy of treatment by assessing macrophage depletion via IBA-1 (a marker for macrophages [28]) staining and flow cytometry analysis.