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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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Thoracic and abdominal aorta media of aged apoE−/− aorta is infiltrated by leukocytes and shows differential loss of integrity. (a) ATLO staining for CD68+ macrophages (left, filled arrows) and CD11c+ macrophages/DCs (right, open arrows) show leukocyte infiltration of inner and outer media. (b) Elastin staining of ATLO-free diseased abdominal aorta shows loss of elastic fiber integrity in the inner media (left arrows), whereas ATLO-associated abdominal aorta shows loss of integrity in inner and outer media (right arrows). Foam cells adjacent to media are often associated with elastin strand breaks (asterisks). (c) FACS-sorted blood monocyte subset (left) microarrays (right) reveal differential Ltb mRNA expression (two-sided unpaired Student's t test; P < 0.0001). Bars, 100 μm.
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fig9: Thoracic and abdominal aorta media of aged apoE−/− aorta is infiltrated by leukocytes and shows differential loss of integrity. (a) ATLO staining for CD68+ macrophages (left, filled arrows) and CD11c+ macrophages/DCs (right, open arrows) show leukocyte infiltration of inner and outer media. (b) Elastin staining of ATLO-free diseased abdominal aorta shows loss of elastic fiber integrity in the inner media (left arrows), whereas ATLO-associated abdominal aorta shows loss of integrity in inner and outer media (right arrows). Foam cells adjacent to media are often associated with elastin strand breaks (asterisks). (c) FACS-sorted blood monocyte subset (left) microarrays (right) reveal differential Ltb mRNA expression (two-sided unpaired Student's t test; P < 0.0001). Bars, 100 μm.

Mentions: Finally, we wondered whether ATLO formation affected the integrity of the aorta, as it has been suggested in humans where B cells within the adventitia of abdominal aortae characterize specimens with aneurysm (42–44). Indeed, ATLOs were associated with leukocyte infiltration, including CD68+ cells, of the abdominal aorta in both the outer and inner media layers (Fig. 9 a, left). Elastin staining indicated erosion of the internal lamina and adjacent elastic membranes in association with atherosclerotic plaques (Fig. 9 b, left arrows). In comparison to thoracic aorta, destruction of abdominal aorta media structure was more pronounced (unpublished data). Erosion of the external lamina was observed in association with ATLOs (Fig. 9 b, right arrows).


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)

Thoracic and abdominal aorta media of aged apoE−/− aorta is infiltrated by leukocytes and shows differential loss of integrity. (a) ATLO staining for CD68+ macrophages (left, filled arrows) and CD11c+ macrophages/DCs (right, open arrows) show leukocyte infiltration of inner and outer media. (b) Elastin staining of ATLO-free diseased abdominal aorta shows loss of elastic fiber integrity in the inner media (left arrows), whereas ATLO-associated abdominal aorta shows loss of integrity in inner and outer media (right arrows). Foam cells adjacent to media are often associated with elastin strand breaks (asterisks). (c) FACS-sorted blood monocyte subset (left) microarrays (right) reveal differential Ltb mRNA expression (two-sided unpaired Student's t test; P < 0.0001). Bars, 100 μm.
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Related In: Results  -  Collection

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

fig9: Thoracic and abdominal aorta media of aged apoE−/− aorta is infiltrated by leukocytes and shows differential loss of integrity. (a) ATLO staining for CD68+ macrophages (left, filled arrows) and CD11c+ macrophages/DCs (right, open arrows) show leukocyte infiltration of inner and outer media. (b) Elastin staining of ATLO-free diseased abdominal aorta shows loss of elastic fiber integrity in the inner media (left arrows), whereas ATLO-associated abdominal aorta shows loss of integrity in inner and outer media (right arrows). Foam cells adjacent to media are often associated with elastin strand breaks (asterisks). (c) FACS-sorted blood monocyte subset (left) microarrays (right) reveal differential Ltb mRNA expression (two-sided unpaired Student's t test; P < 0.0001). Bars, 100 μm.
Mentions: Finally, we wondered whether ATLO formation affected the integrity of the aorta, as it has been suggested in humans where B cells within the adventitia of abdominal aortae characterize specimens with aneurysm (42–44). Indeed, ATLOs were associated with leukocyte infiltration, including CD68+ cells, of the abdominal aorta in both the outer and inner media layers (Fig. 9 a, left). Elastin staining indicated erosion of the internal lamina and adjacent elastic membranes in association with atherosclerotic plaques (Fig. 9 b, left arrows). In comparison to thoracic aorta, destruction of abdominal aorta media structure was more pronounced (unpublished data). Erosion of the external lamina was observed in association with ATLOs (Fig. 9 b, right arrows).

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