Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.
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.
Gräbner
Rolf
R
Institute for Vascular Medicine, Friedrich Schiller University of Jena, 07743 Jena, Germany.
Lötzer
Katharina
K
Döpping
Sandra
S
Hildner
Markus
M
Radke
Dörte
D
Beer
Michael
M
Spanbroek
Rainer
R
Lippert
Beatrix
B
Reardon
Catherine A
CA
Getz
Godfrey S
GS
Fu
Yang-Xin
YX
Hehlgans
Thomas
T
Mebius
Reina E
RE
van der Wall
Michael
M
Kruspe
Dagmar
D
Englert
Christoph
C
Lovas
Agnes
A
Hu
Desheng
D
Randolph
Gwendalyn J
GJ
Weih
Falk
F
Habenicht
Andreas J R
AJ
D000375:Aging; D000818:Animals; D001012:Aorta, Abdominal / Q000254:growth & development* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics; D001692:Biological Transport; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D003238:Connective Tissue / Q000254:growth & development* / Q000378:metabolism; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D017539:Tunica Intima / Q000254:growth & development / Q000378:metabolism; D017540:Tunica Media / Q000254:growth & development / Q000378:metabolism
D001057:Apolipoproteins E; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D053259:Lymphotoxin beta Receptor