Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice
Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice
复制标题
DOI：
10.4049/jimmunol.1402342
复制
发表时间：
2015-04-15
影响因子：
4.4
通讯作者：
Toure, Fatouma
中科院分区：
文献类型：
--
作者：
Goury, Antoine;Meghraoui-Kheddar, Aida;Toure, Fatouma
晚期糖基化终产物受体（RAGE）是一种模式识别受体，它与晚期糖基化终产物相互作用，但也与C3a、CpG DNA寡核苷酸和HMGB1等报警蛋白分子相互作用，以启动促炎反应。系统性红斑狼疮是一种与RAGE配体积累相关的自身免疫性疾病。我们在狼疮易发B6-MRL Fas lpr/j背景下产生RAGE无效的小鼠，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野生型和B6-MRL Fas lpr/j幼崽的表型进行了比较。与B6-MRL Fas lpr/j小鼠相比，B6-MRL Fas lpr/j小鼠淋巴细胞增生性综合征、抗dsdna抗体的产生、狼疮性肾炎和CD3(+)B220(+)CD4(-)CD8（-）自身反应性T细胞（外周血和脾脏）的积累（-/-）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小鼠的大量自身反应性T细胞在其表面表达RAGE。膜联蛋白V表达的时间过程研究表明，B6-MRL Fas lpr/j- rage（-/-）小鼠脾脏的自身反应性T细胞凋亡延迟，活化的caspase 3表达量（39.5 +/- 4.3%）明显低于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，在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，从而加剧了淋巴增生性综合征、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。
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.