Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling.
Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling.
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DOI：
10.1161/atvbaha.109.191395
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发表时间：
2010-03
期刊：
影响因子：
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通讯作者：
Habenicht AJ
中科院分区：
文献类型：
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作者：
Lötzer K;Döpping S;Connert S;Gräbner R;Spanbroek R;Lemser B;Beer M;Hildner M;Hehlgans T;van der Wall M;Mebius RE;Lovas A;Randolph GJ;Weih F;Habenicht AJ
小鼠主动脉平滑肌细胞（SMC）表达肿瘤坏死因子受体超家族成员1A（TNFR-1）和光敏素β受体（LTβR）。间接证据表明，SMC LTβR与高脂血症小鼠的三级淋巴器官发生有关。在此，我们探讨了TNFR-1和LTβR信号在培养SMC中的作用。TNFR-1信号激活经典的RelA NF-κB通路，而LTβR信号激活经典的RelA和替代的RelB NF-κB通路，并且两种信号通路协同增强p100抑制剂对NF-κB的p52亚基的加工。基因芯片显示TNFR-1/LTβR同时激活导致白细胞稳态趋化因子CCL 2、CCL 5、CXCL 1和CX 3CL 1的mRNA表达升高。重要的是，SMC获得了淋巴组织者的特征，其通过过度诱导CCL 7、CCL 9、CXCL 13、CCL 19、CXCL 16、血管细胞粘附分子-1和细胞间粘附分子-1来控制自身免疫性疾病中的三级淋巴器官发生。TNFR-1/LTβR相互作用导致淋巴器官生成趋化因子蛋白分泌增加。TNFR-1/LTβ R激活的SMC上清明显支持脾T细胞、B细胞和巨噬细胞/树突状细胞的迁移。用ltbr−/− SMC进行的实验表明，LTβR-RelB激活是产生淋巴组织组织形成者表型的必要条件。SMC可能通过上调与T淋巴细胞、B淋巴细胞和巨噬细胞/树突状细胞吸引有关的淋巴器官趋化因子参与动脉粥样硬化中三级淋巴组织的形成。
Mouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin β-receptor (LTβR). Circumstantial evidence has linked the SMC LTβR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTβR signaling in cultured SMC. TNFR-1 signaling activated the classical RelA NF-κB pathway, whereas LTβR signaling activated the classical RelA and alternative RelB NF-κB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB. Microarrays showed that simultaneous TNFR-1/LTβR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of lymphoid tissue organizers, which control tertiary lymphoid organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTβR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTβR–activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr−/− SMC indicated that LTβR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype. SMC may participate in the formation of tertiary lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.