CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Abstract

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4+ T cells, Ly6C+ monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

“…Previous study found that some monocyte chemokines, such as MCP-1 (monocyte chemotactic protein 1), CCL (CC chemokine ligand) 3, CCL4 and CCL5 contributed to migration of immature myeloid cells [29,30], which were increased in lupus-prone mice [31]. We found that the expression of MCP-1, CCL3, CCL4 and CCL5 was all increased in spleen ( Figure 5A) and PBMCs ( Figure 5B pathogenesis [32], but also were critical for recruitment of neutrophils [33,34] and MDSCs [35]. Expression of CCR1 and CCR5 in splenic G-MDSCs and M-MDSCs was measured.…”

CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity‐associated cancer

“…Also, the chemokines macrophage chemoattractant protein 1 (MCP‐1) and regulated on activation normal T cell expressed and secreted (RANTES) and their chemokine receptors CCR2 and CCR5 have been implicated in macrophage and T cell trafficking to visceral adipose tissue 9 , 10 . While the chemokine system facilitates normal immune function and directs immune cells to sites of infection or malignancy, the expression of chemokines and their receptors on pro‐inflammatory T cells have also been implicated in inflammatory diseases such as asthma, lupus nephritis and arthritis 11 , 12 , 13 . The role of chemokines in obesity associated pathologies is an area of emerging interest 14 , 15 , 16 , 17 …”

The Pathogenesis of Lupus Nephritis

“…In children with active lupus nephritis, intravenous methyl-prednisolone pulse therapy was shown to restore CD4 + FoxP3 + and CD8 + Foxp3 + T regulatory cell levels, and treated CD8 + FoxP3 + T regulatory cells suppressed CD4 + T cell proliferation and induced their apoptosis, modulating autoimmune response in lupus nephritis [69]. The Ccr1 chemokine receptor is associated with leukocyte infiltration with NZB/W mice with nephritis being more responsive to Ccr1 ligand and subsequent T cell, mononuclear phagocytes, and neutrophil influx than pre-nephritic mice [70]. Treatment with a Ccr1 antagonist decreased accumulation of effector CD4 + T cells, memory CD4 + T cells, Ly6C + monocytes, M1 macrophages, and M2 macrophages; decreased tubulointerstial and glomerular damage; slowed the onset of proteinuria; extended life-span; but had no therapeutic effect in slowing the infiltration of B cells, insinuating that Ccr1 is important for the recruitment of T cells and mononuclear phagocyte cells [70].…”

“…The Ccr1 chemokine receptor is associated with leukocyte infiltration with NZB/W mice with nephritis being more responsive to Ccr1 ligand and subsequent T cell, mononuclear phagocytes, and neutrophil influx than pre-nephritic mice [70]. Treatment with a Ccr1 antagonist decreased accumulation of effector CD4 + T cells, memory CD4 + T cells, Ly6C + monocytes, M1 macrophages, and M2 macrophages; decreased tubulointerstial and glomerular damage; slowed the onset of proteinuria; extended life-span; but had no therapeutic effect in slowing the infiltration of B cells, insinuating that Ccr1 is important for the recruitment of T cells and mononuclear phagocyte cells [70]. CD147 is a glycosylated transmembrane protein that plays a role in regulating lymphocyte response and leukocyte influx, it is induced in injured glomeruli and incoming inflammatory cells, and plasma levels reflect histological disease activity, making it a good potential biomarker in lupus nephritis patients [71] (Figure 2).…”