Goury Antoine, Meghraoui-Kheddar Aïda, Belmokhtar Karim, Vuiblet Vincent, Ortillon Jeremy, Jaisson Stéphane, Devy Jerôme, Le Naour Richard, Tabary Thierry, Cohen Jacques H M, Schmidt Ann-Marie, Rieu Philippe, Touré Fatouma
Faculté de Médecine, Laboratoire de Néphrologie, Université de Reims Champagne-Ardenne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7369 (Matrice Extracellulaire et Dynamique Cellulaire), 51100 Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire de Reims, 51100 Reims, France;
Faculté de Pharmacie, Université de Reims Champagne-Ardenne, EA4683 (Immunité Adaptative et Fonctionnalité des Barrières Biologiques), 51100 Reims, France;
J Immunol. 2015 Apr 15;194(8):3612-22. doi: 10.4049/jimmunol.1402342. Epub 2015 Mar 11.
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. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. 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. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. 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). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. 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). 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. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.
晚期糖基化终末产物受体（RAGE）是一种模式识别受体，它不仅能与晚期糖基化终末产物相互作用，还能与C3a、CpG DNA寡核苷酸以及警报素分子（如HMGB1）相互作用，从而引发促炎反应。系统性红斑狼疮是一种与RAGE配体积聚相关的自身免疫性疾病。我们在易患狼疮的B6-MRL Fas lpr/j背景下培育出RAGE基因缺失的小鼠，以确定RAGE在系统性红斑狼疮发病机制中的作用。我们将这些小鼠的表型与其野生型和B6-MRL Fas lpr/j同窝小鼠的表型进行了比较。与B6-MRL Fas lpr/j小鼠相比，B6-MRL Fas lpr/j RAGE(-/-)小鼠的淋巴细胞增殖综合征、抗双链DNA抗体的产生、狼疮性肾炎以及外周血和脾脏中CD3(+)B220(+)CD4(-)CD8(-)自身反应性T细胞的积累均显著增加（分别为p < 0.005、p < 0.05、p < 0.001和p < 0.001）。来自B6-MRL Fas lpr/j小鼠的大部分自身反应性T细胞在其表面表达RAGE。膜联蛋白V表达的时间进程研究表明，B6-MRL Fas lpr/j-RAGE(-/-)小鼠脾脏中的自身反应性T细胞凋亡延迟，且活化的半胱天冬酶3表达显著低于B6-MRL Fas lpr/j小鼠（65.5 ± 5.2%）或野生型小鼠（75.3 ± 2.64%）（p = 0.02）。我们得出结论，B6-MRL Fas lpr/j小鼠中RAGE的缺失促进了自身反应性CD3(+)B220(+)CD4(-)CD8(-)T细胞的积累，从而加剧了淋巴细胞增殖综合征、自身免疫和器官损伤。这表明当死亡受体Fas/CD95功能失调时，RAGE可挽救T淋巴细胞的凋亡。
