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

Gräbner R, Lötzer K, Döpping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJ - J. Exp. Med. (2009)

Bottom Line: 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 LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs.Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

View Article: PubMed Central - PubMed

Affiliation: Institute for Vascular Medicine, Friedrich Schiller University of Jena, 07743 Jena, Germany.

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 beta receptor (LTbetaR) 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 LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

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Incidence of ATLOs in different aorta segments and association of ATLOs and plaques. (a) Preferential occurrence of ATLOs in the abdominal aorta; innominate arteries and abdominal aortae were examined for ATLO stages in aged apoE−/− mice. chi-Square (χ2) test, P < 0.02. (b) ATLO sizes correlate with plaque sizes; morphometry was performed by determination of plaque size/media size or ATLO size/media size (n = 11 mice). Pearson correlation coefficient: 0.783. P < 0.01.
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fig1: Incidence of ATLOs in different aorta segments and association of ATLOs and plaques. (a) Preferential occurrence of ATLOs in the abdominal aorta; innominate arteries and abdominal aortae were examined for ATLO stages in aged apoE−/− mice. chi-Square (χ2) test, P < 0.02. (b) ATLO sizes correlate with plaque sizes; morphometry was performed by determination of plaque size/media size or ATLO size/media size (n = 11 mice). Pearson correlation coefficient: 0.783. P < 0.01.

Mentions: We searched for ATLOs in 6–130-wk-old mice (n = 30) using a three-stage classification scheme (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20080752/DC1). ATLO neogenesis was initiated at >32 wk and occurred in ∼75% of mice afflicted with abdominal aorta atherosclerosis at 78 wk. We compared ATLO incidence in the innominate artery with the incidence in the abdominal aorta at 78 wk. Most (8/11) apoE−/− mice developed ATLO stage II/III in the abdominal aorta, whereas only 1/11 mice showed a stage I ATLO in the innominate artery (Fig. 1 a). We never observed ATLO formation in aorta segments that were not affected by lesions. Moreover, lesion sizes in the abdominal aorta correlated with ATLO sizes (Fig. 1 b).


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

Gräbner R, Lötzer K, Döpping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJ - J. Exp. Med. (2009)

Incidence of ATLOs in different aorta segments and association of ATLOs and plaques. (a) Preferential occurrence of ATLOs in the abdominal aorta; innominate arteries and abdominal aortae were examined for ATLO stages in aged apoE−/− mice. chi-Square (χ2) test, P < 0.02. (b) ATLO sizes correlate with plaque sizes; morphometry was performed by determination of plaque size/media size or ATLO size/media size (n = 11 mice). Pearson correlation coefficient: 0.783. P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626665&req=5

fig1: Incidence of ATLOs in different aorta segments and association of ATLOs and plaques. (a) Preferential occurrence of ATLOs in the abdominal aorta; innominate arteries and abdominal aortae were examined for ATLO stages in aged apoE−/− mice. chi-Square (χ2) test, P < 0.02. (b) ATLO sizes correlate with plaque sizes; morphometry was performed by determination of plaque size/media size or ATLO size/media size (n = 11 mice). Pearson correlation coefficient: 0.783. P < 0.01.
Mentions: We searched for ATLOs in 6–130-wk-old mice (n = 30) using a three-stage classification scheme (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20080752/DC1). ATLO neogenesis was initiated at >32 wk and occurred in ∼75% of mice afflicted with abdominal aorta atherosclerosis at 78 wk. We compared ATLO incidence in the innominate artery with the incidence in the abdominal aorta at 78 wk. Most (8/11) apoE−/− mice developed ATLO stage II/III in the abdominal aorta, whereas only 1/11 mice showed a stage I ATLO in the innominate artery (Fig. 1 a). We never observed ATLO formation in aorta segments that were not affected by lesions. Moreover, lesion sizes in the abdominal aorta correlated with ATLO sizes (Fig. 1 b).

Bottom Line: 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 LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs.Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

View Article: PubMed Central - PubMed

Affiliation: Institute for Vascular Medicine, Friedrich Schiller University of Jena, 07743 Jena, Germany.

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 beta receptor (LTbetaR) 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 LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

Show MeSH
Related in: MedlinePlus