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

Rolf Gräbner, Katharina Lötzer, Sandra Döpping, Markus Hildner, Dörte Radke, Michael Beer, Rainer Spanbroek, Beatrix Lippert, Catherine A. Reardon, Godfrey S. Getz, Yang Xin Fu, Thomas Hehlgans, Reina E. Mebius, Michael Der Van Wall, Dagmar Kruspe, Christoph Englert, Agnes Lovas, Desheng Hu, Gwendalyn J. Randolph, Falk WeihAndreas J.R. Habenicht

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233 Scopus citations

Abstract

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 β receptor (LTβR) 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 endothe- lial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE -/- mice with LTβR-Ig to interrupt LTβR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTβR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

Original languageEnglish
Pages (from-to)233-248
Number of pages16
JournalJournal of Experimental Medicine
Volume206
Issue number1
DOIs
StatePublished - Jan 16 2009
Externally publishedYes

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    Gräbner, R., Lötzer, K., Döpping, S., Hildner, M., Radke, D., Beer, M., Spanbroek, R., Lippert, B., Reardon, C. A., Getz, G. S., Fu, Y. X., Hehlgans, T., Mebius, R. E., Van Wall, M. D., Kruspe, D., Englert, C., Lovas, A., Hu, D., Randolph, G. J., ... Habenicht, A. J. R. (2009). Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE -/- mice. Journal of Experimental Medicine, 206(1), 233-248. https://doi.org/10.1084/jem.20080752