Rodent rage fot12/29/2023 ![]() All experiments were approved by the ethics committee for animal care and use of Reims Champagne Ardenne (CEEA-RCA-56). RAGE −/− mice were backcrossed for >20 generations in the C57BL/6 background. In this study, we describe the phenotypic characteristics associated with RAGE deletion in this genetic background and suggest a possible underlying mechanism to account for this phenotype.Ĭ57BL/6 and B6-MRL Fas lpr/j mice were purchased from Charles River Laboratories. We generated RAGE knockout mice in the B6-MRL Fas lpr/j background to investigate the role of RAGE in the physiopathology of SLE. Autoantibody concentration is high in B6-MRL Fas lpr/j mice that spontaneously develop massive lymphoproliferation and the visceral manifestations of SLE ( 19, 20). One such model is the homozygous Murphy Roths large/lymphoproliferation mouse (B6-MRL/lpr or B6-MRL Fas lpr/j mice), which carries a loss of function mutation in the death receptor Fas/CD95 gene. This feature is recapitulated in animal models. Thus, the aberrant survival of lymphocytes is a prominent feature of the disease. Indeed, the defective removal of dead cells increases exposition to nuclear materials, whereas the presence of abnormally long-lived T and B cell clones accounts for the increased production of anti-nuclear Abs, immune complex disease, and T cell–dependent tissue damage ( 16– 18). Loss of self-tolerance to ubiquitous nuclear Ags is the underlying pathogenic mechanism leading to immunization ( 14, 15). Systemic lupus erythematosus (SLE) is an autoimmune disease that affects several organs, such as the heart, skin, and kidneys ( 12, 13). Therefore, RAGE signaling is involved in the pathogenesis of several diseases, including vascular and neurodegenerative diseases, diabetes, cancer, and autoimmune disorders ( 8– 11). RAGE was first described as a binding partner for advanced glycation end products (AGEs) ( 3, 4) however, proteins from the S100 family, amyloid fibrils, high mobility group box 1 (HMGB1), C3a, and CpG DNA oligonucleotides are able to trigger a proinflammatory response via RAGE ( 5– 7). ![]() Receptor for advanced glycation end products (RAGE) is a cell surface receptor of the Ig superfamily and is involved in seminal processes such as cell migration, adhesion, and proliferation ( 1, 2). This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional. We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3 +B220 +CD4 −CD8 − T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. ![]() Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE −/− mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) ( p = 0.02). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3 +B220 +CD4 −CD8 − autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE −/− mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). ![]() We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction.
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