Absence of the lysosomal protein Limp‐2 attenuates renal injury in crescentic glomerulonephritis

Abstract

In humans, mutations of the intrinsic lysosomal protein SCARB2 are associated with myoclonic epilepsy, collapsing focal and segmental glomerulosclerosis, and tubular proteinuria. Mice with deficiency of Limp-2 (the murine homologue) develop tubular proteinuria but not focal and segmental glomerulosclerosis and they have a defect in macrophage function. To further elucidate the role of Limp-2 in immune function, we induced anti-glomerular basement membrane (GBM) model of crescentic glomerulonephritis in wild-type (WT) and Limp-2(-/-) littermates by intraperitoneal injections of nephrotoxic sheep serum. Renal injury and immune responses were assessed on day 14. Compared with WT, Limp-2(-/-) mice had significantly reduced crescent formation, interstitial inflammation and a trend to reduced tubulointerstitial injury. On day 1 during the heterologous phase of the disease, albuminuria was significantly increased in WT but not in Limp-2(-/-) mice. On day 14, albuminuria and renal function were similar in the two groups. There was, however, a significant reduction in the influx of glomerular macrophages and CD4(+) T cells in Limp-2(-/-) mice. Interleukin (IL)-4 and macrophage chemoattractant protein-1 (MCP-1) mRNA expression levels were significantly reduced. Despite the reduction in numbers of infiltrating cells, flow cytometry showed no difference in macrophage or T-cell numbers in the peripheral blood from untreated mice. The systemic humoral immune response, determined by glomerular mouse immunoglobulin G (IgG) deposition and mouse anti-sheep IgG subclass production, was similar in both groups. These data suggest that absence of Limp-2 reduces inflammation in experimental crescentic glomerulonephritis with decreased macrophage and T-cell infiltration in the kidney. It suggests an important role for Limp-2 in mediating the inflammatory response.

Novel autoantibodies help diagnose anti-SSA antibody negative Sjögren disease and predict abnormal labial salivary gland pathology

“…SCRB2 is a lysosomal receptor for glucosylceramidase37 and a receptor for enterovirus 38. The absence of SCRB2 decreases macrophage and T-cell response in mouse models of crescentic glomerulonephritis39 and Listeria infection 40. It is unclear how IgG that recognises linear epitopes in these proteins might contribute to SjD; indeed, it is not known if full-length proteins are bound by these autoantibodies.…”

Novel autoantibodies help diagnose anti-SSA antibody negative Sjögren’s disease and predict abnormal labial salivary gland pathology

“…SCRB2 is a lysosomal receptor for glucosylceramidase [32] and a receptor for enterovirus [33]. The absence of SCRB2 decreases macrophage and T-cell response in mouse models of crescentic glomerulonephritis [34] and Listeria infection [35]. It is unclear how IgG that recognizes linear epitopes in these proteins might contribute to SjD; indeed, it is not known if full-length proteins are bound by these autoantibodies.…”

Lysosome function in glomerular health and disease

“…Besides the abovementioned potential involvement of autoantibodies to LAMP2 in the pathogenesis of crescentic GN, a study performed in Limp2-deficient mice highlights a pro-inflammatory involvement of lysosomes in the anti-glomerular basement membrane model of crescentic GN, as Limp2-deficient mice exhibit a decreased renal infiltration of macrophages and T cells (Lee et al 2014 ). This could relate to a blockage of the lysosomal involvement in driving inflammation through lysosomal exocytosis and inflammasome activation.…”