M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis
M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis
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DOI：
10.1093/cvr/cvt263
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发表时间：
2014-03-01
影响因子：
10.8
通讯作者：
Nicoletti, Antonino
中科院分区：
文献类型：
--
作者：
Guedj, Kevin;Khallou-Laschet, Jamila;Nicoletti, Antonino
目的本研究的目的是描述炎症巨噬细胞在诱导血管平滑肌细胞（VSMC）介导的主动脉三级淋巴器官（TLOs）形成中的作用。方法和结果小鼠骨髓源性M1巨噬细胞作为淋巴组织诱导细胞。事实上，它们表达高水平的肿瘤坏死因子（TNF）-α和膜结合淋巴毒素（LT）-α，这两种诱导细胞因子触发趋化因子CCL 19、CCL 20和CXCL 16的表达，M1上清液也是如此。用LT β R-Ig阻断LT β R信号传导没有效果，而TNFR 1/ 2信号传导降低了野生型（WT）和LT β R KO小鼠中VSMC的趋化因子表达，表明LT β R信号传导与M1诱导效应无关。原位移植后在LT β R KO->载脂蛋白E敲除（ApoE KO）主动脉节段中观察到的TLO发展证实了这一效应。此外，用抗TNF-α抗体处理ApoE KO小鼠可降低主动脉TLO的数量和发生率。最后，淋巴结组成的T和B细胞形成在体内植入支架接种VSMCs以前刺激离体M1-条件medium.Conclusions这些结果是第一次确定M1巨噬细胞作为诱导细胞，触发VSMCs独立的LT β R信号的趋化因子的表达。我们认为巨噬细胞和血管平滑肌细胞之间的对话--跨血管壁建立--有助于主动脉TLO的形成。
Aims The goal of this study was to characterize the role of inflammatory macrophages in the induction of the vascular smooth muscle cell (VSMC)-mediated formation of aortic tertiary lymphoid organs (TLOs).Methods and results Mouse bone marrow-derived M1 macrophages acted as lymphoid tissue inducer cells. Indeed, they expressed high levels of tumour necrosis factor (TNF)-alpha and membrane-bound lymphotoxin (LT)-alpha, two inducing cytokines that triggered expression of the chemokines CCL19, CCL20, and CXCL16, as did M1 supernatant. The blockade of LT beta R signalling with LT beta R-Ig had no effect, whereas that of TNFR1/ 2 signalling reduced chemokine expression by VSMCs in both wild-type (WT) and LT beta R KO mice, demonstrating that LT beta R signalling is dispensable for the M1-inducing effect. This effect was corroborated by the development of TLOs observed in LT beta R KO->apolipoprotein E knockout (ApoE KO) aortic segments after orthotopic transplantation. Furthermore, treatment of ApoE KOmice with anti-TNF-alpha antibody decreased the number and incidence of aortic TLOs. Finally, lymphoid nodules composed of T and B cells formed in in vivo-implanted scaffolds seeded with VSMCs previously stimulated ex vivo by M1-conditioned medium.Conclusions These results are the first to identify M1 macrophages as inducer cells that trigger the expression of chemokines by VSMCsindependently of LT beta R signalling. We propose that the dialogue betweenmacrophages andVSMCs-established across the vascular wall-contributes to the formation of aortic TLOs.