Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice

被引：312

作者：

Graebner, Rolf ^{[1
]}

Loetzer, Katharina ^{[1
]}

Doepping, Sandra ^{[1
]}

Hildner, Markus ^{[1
]}

Radke, Doerte ^{[1
]}

Beer, Michael ^{[1
]}

Spanbroek, Rainer ^{[1
]}

Lippert, Beatrix ^{[1
]}

Reardon, Catherine A. ^{[3
]}

Getz, Godfrey S. ^{[3
]}

Fu, Yang-Xin ^{[3
]}

Hehlgans, Thomas ^{[4
]}

Mebius, Reina E. ^{[5
]}

van der Wall, Michael ^{[2
]}

Kruspe, Dagmar ^{[6
]}

Englert, Christoph ^{[6
]}

Lovas, Agnes ^{[7
]}

Hu, Desheng ^{[7
]}

Randolph, Gwendalyn J. ^{[8
]}

Weih, Falk ^{[7
]}

Habenicht, Andreas J. R. ^{[1
]}

机构：

[1] Univ Jena, Inst Vasc Med, D-07743 Jena, Germany

[2] Univ Jena, Anim Res Inst, D-07743 Jena, Germany

[3] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[4] Univ Regensburg, Inst Immunol, D-93053 Regensburg, Germany

[5] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, NL-1007 MB Amsterdam, Netherlands

[6] Fritz Lipmann Inst, Res Grp Mol Genet, Leibniz Inst Age Res, D-07745 Jena, Germany

[7] Fritz Lipmann Inst, Leibniz Inst Age Res, Res Grp Immunol, D-07745 Jena, Germany

[8] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2009年 / 206卷 / 01期

基金：

美国国家卫生研究院;

关键词：

FOLLICULAR DENDRITIC CELLS; SMOOTH-MUSCLE-CELLS; REGULATORY T-CELLS; E-DEFICIENT MICE; B-CELLS; LASER MICRODISSECTION; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASE; ORGAN DEVELOPMENT; IMMUNE-RESPONSES;

D O I：

10.1084/jem.20080752

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE(-/-) mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin beta receptor (LT beta R) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE(-/-) mice with LT beta R-Ig to interrupt LT beta R signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LT beta R pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

引用

页码：233 / 248

页数：16

共 78 条

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