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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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Media SMCs sandwiched between lesions and ATLOs are activated and express the lymphorganogenic chemokines CXCL13 and CCL21. (a) CXCL13 and CCL21 of ATLO-burdened aorta segment (top). Media SMCs and cells with DC morphology stain positive for CXCL13 in B cell follicle (top left, open triangles) and for CCL21 in T cell area (top right, filled arrows), whereas SMCs of aorta segments without adjacent ATLO (thoracic aorta with plaque) do not (bottom). Medium-sized ATLO blood vessels stain positive for CCL21 (top right, filled arrows), whereas small blood vessels (top right, open arrows) in B cell follicles are CCL21−. L, lymph vessel; P, plaque. (b) Colocalization of SMA and CXCL13 and SMA and CCL21 with VCAM-1 in abdominal aorta segments adjacent to ATLO. Bars, 100 μm.
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fig6: Media SMCs sandwiched between lesions and ATLOs are activated and express the lymphorganogenic chemokines CXCL13 and CCL21. (a) CXCL13 and CCL21 of ATLO-burdened aorta segment (top). Media SMCs and cells with DC morphology stain positive for CXCL13 in B cell follicle (top left, open triangles) and for CCL21 in T cell area (top right, filled arrows), whereas SMCs of aorta segments without adjacent ATLO (thoracic aorta with plaque) do not (bottom). Medium-sized ATLO blood vessels stain positive for CCL21 (top right, filled arrows), whereas small blood vessels (top right, open arrows) in B cell follicles are CCL21−. L, lymph vessel; P, plaque. (b) Colocalization of SMA and CXCL13 and SMA and CCL21 with VCAM-1 in abdominal aorta segments adjacent to ATLO. Bars, 100 μm.

Mentions: Because embryonic SLO formation requires CXCL13 and CCL21 chemokines (24–26), and ectopic expression of CXCL13 is sufficient to induce TLOs (27), we searched for CXCL13/CCL21 in ATLOs. Surprisingly, media segments sandwiched between lesions and ATLOs expressed CXCL13 and CCL21 (Fig. 6 a, top). In contrast, the media of the thoracic aorta of apoE−/− mice (Fig. 6 a, bottom), the media of the abdominal aorta of apoE−/− mice without adjacent lesions, and the media of the entire aorta of wild-type mice (not depicted) were CXCL13−CCL21− or CXCL13dimCCL21−. CXCL13 and CCL21 colocalized with smooth muscle actin (SMA) and SMAdim myofibroblasts, which may represent dedifferentiated SMCs (Fig. 6 b, top). Both CXCL13 and CCL21 colocalized with VCAM-1, indicating that CXCL13+ and CCL21+ SMCs were activated (Fig. 6 b, bottom). In addition to media SMCs, fibroblast-like cells with DC morphology in ATLO B cell follicles were CXCL13+ (Fig. 6 a), and Lyve1+ lymph vessels (L) and larger MECA-32+ blood vessels (arrows) in ATLO T cell areas expressed CCL21. Thus, the media separating plaques and ATLOs becomes modified, containing activated SMCs that express the lymphorganogenic chemokines CXCL13 and CCL21. This activation may be an organizing event by which SMCs support the development and maintenance of ATLOs.


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)

Media SMCs sandwiched between lesions and ATLOs are activated and express the lymphorganogenic chemokines CXCL13 and CCL21. (a) CXCL13 and CCL21 of ATLO-burdened aorta segment (top). Media SMCs and cells with DC morphology stain positive for CXCL13 in B cell follicle (top left, open triangles) and for CCL21 in T cell area (top right, filled arrows), whereas SMCs of aorta segments without adjacent ATLO (thoracic aorta with plaque) do not (bottom). Medium-sized ATLO blood vessels stain positive for CCL21 (top right, filled arrows), whereas small blood vessels (top right, open arrows) in B cell follicles are CCL21−. L, lymph vessel; P, plaque. (b) Colocalization of SMA and CXCL13 and SMA and CCL21 with VCAM-1 in abdominal aorta segments adjacent to ATLO. Bars, 100 μm.
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fig6: Media SMCs sandwiched between lesions and ATLOs are activated and express the lymphorganogenic chemokines CXCL13 and CCL21. (a) CXCL13 and CCL21 of ATLO-burdened aorta segment (top). Media SMCs and cells with DC morphology stain positive for CXCL13 in B cell follicle (top left, open triangles) and for CCL21 in T cell area (top right, filled arrows), whereas SMCs of aorta segments without adjacent ATLO (thoracic aorta with plaque) do not (bottom). Medium-sized ATLO blood vessels stain positive for CCL21 (top right, filled arrows), whereas small blood vessels (top right, open arrows) in B cell follicles are CCL21−. L, lymph vessel; P, plaque. (b) Colocalization of SMA and CXCL13 and SMA and CCL21 with VCAM-1 in abdominal aorta segments adjacent to ATLO. Bars, 100 μm.
Mentions: Because embryonic SLO formation requires CXCL13 and CCL21 chemokines (24–26), and ectopic expression of CXCL13 is sufficient to induce TLOs (27), we searched for CXCL13/CCL21 in ATLOs. Surprisingly, media segments sandwiched between lesions and ATLOs expressed CXCL13 and CCL21 (Fig. 6 a, top). In contrast, the media of the thoracic aorta of apoE−/− mice (Fig. 6 a, bottom), the media of the abdominal aorta of apoE−/− mice without adjacent lesions, and the media of the entire aorta of wild-type mice (not depicted) were CXCL13−CCL21− or CXCL13dimCCL21−. CXCL13 and CCL21 colocalized with smooth muscle actin (SMA) and SMAdim myofibroblasts, which may represent dedifferentiated SMCs (Fig. 6 b, top). Both CXCL13 and CCL21 colocalized with VCAM-1, indicating that CXCL13+ and CCL21+ SMCs were activated (Fig. 6 b, bottom). In addition to media SMCs, fibroblast-like cells with DC morphology in ATLO B cell follicles were CXCL13+ (Fig. 6 a), and Lyve1+ lymph vessels (L) and larger MECA-32+ blood vessels (arrows) in ATLO T cell areas expressed CCL21. Thus, the media separating plaques and ATLOs becomes modified, containing activated SMCs that express the lymphorganogenic chemokines CXCL13 and CCL21. This activation may be an organizing event by which SMCs support the development and maintenance of ATLOs.

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