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

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that can affect multiple end organs. Kidney and brain are two of the organs most commonly involved in SLE. Past studies have suggested the importance of macrophages in the pathogenesis of lupus nephritis (LN). Furthermore, as the immune effectors of the brain, microglia have been implicated in pathways leading to neuropsychiatric SLE (NPSLE). We depleted macrophages and microglia using GW2580, a small colony stimulating factor-1 receptor (CSF-1R) kinase inhibitor, in MRL-lpr/lpr (MRL/lpr) mice, a classic murine lupus model that displays features of both LN and NPSLE. Treatment was initiated before the onset of disease, and mice were followed for the development of LN and neurobehavioral dysfunction throughout the study. Treatment with GW2580 significantly ameliorated kidney disease, as evidenced by decreased proteinuria, BUN, and improved renal histopathology, despite equivalent levels of IgG and C3 deposition in the kidneys of treated and control mice. We were able to confirm macrophage depletion within the kidney via IBA-1 staining. Furthermore, we observed specific improvement in the depression-like behavioral deficit of MRL/lpr mice with GW2580 treatment. Circulating antibody and autoantibody levels were, however, not affected. These results provide additional support for the role of macrophages as a potentially valuable therapeutic target in SLE. Inhibiting CSF-1 receptor signaling would be more targeted than current immunosuppressive therapies, and may hold promise for the treatment of renal and neuropsychiatric end organ disease manifestations.

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

“…In addition, our DON prodrug was found to completely normalize the glutaminase activity in CD11b + cells, while having no effect on non-CD11b + cells. Consistently, recent studies demonstrated the importance of microglia-associated mechanisms for stress-induced behavioral outcomes in mice models [64,87,88]. These results support our hypothesis that specific upregulation of glutaminase activity in these immune cells in the prefrontal cortex and hippocampus, critical for mood regulation, may contribute to the observed depression-associated phenotypes in CSDS mice, although the mechanism by which CSDS selectively activates glutaminase in CD11b + cells remains elusive.…”

Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis

“…Given that innate immune cells drive disease, as observed in Rag1 -/mice and with LysMCre-mediated ABIN1 deletion, it appears that 3 largely independent effector mechanisms can be differentiated, i.e., PMo-mediated GN, autoimmunity, and systemic inflammation, the latter of which may be mediated primarily by the LysMCre-targeted monocyte/macrophage lineage (Figure 10). Consistent with an important role of this lineage, treatment of MRL/lpr mice with a small-molecule inhibitor of macrophage-CSF receptordriven (M-CSF receptor-driven) monocyte/macrophage generation ameliorated kidney pathology and neuropsychiatric disease, without affecting autoreactive Ab titers; other parameters including splenomegaly and survival were not assessed in that study (53).…”

CSF1R Inhibition Reduces Microglia Proliferation, Promotes Tissue Preservation and Improves Motor Recovery After Spinal Cord Injury

“…Furthermore, a recent report using stab wound brain injury in transgenic mouse model with reduced monocyte invasion reported a strong increase in astrocyte proliferation (Frik et al, 2018 ). Additionally, GW2580 had been delivered orally to a mouse model of systemic lupus erythematosus that display features of lupus nephritis and neuropsychiatric systemic lupus erythematosus involving macrophages and microglia, respectively (Chalmers et al, 2017 ). GW2580-treated mice displayed macrophage depletion within kidneys and decreased levels of several proinflammatory cytokines associated with improved renal histopathology, attenuated disease evolution and ameliorated depression-like behavior.…”