Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling.
OBJECTIVE
Mouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin beta-receptor (LTbetaR). Circumstantial evidence has linked the SMC LTbetaR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTbetaR signaling in cultured SMC.


RESULTS
TNFR-1 signaling activated the classical RelA NF-kappaB pathway, whereas LTbetaR signaling activated the classical RelA and alternative RelB NF-kappaB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-kappaB. Microarrays showed that simultaneous TNFR-1/LTbetaR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of lymphoid tissue organizers, which control tertiary lymphoid organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTbetaR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTbetaR-activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr(-/-) SMC indicated that LTbetaR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype.


CONCLUSIONS
SMC may participate in the formation of tertiary lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.
Institute for Vascular Medicine, Friedrich Schiller University of Jena, Bachstrasse 18, 07743 Jena, Germany.
Katharina
K
Lötzer
Sandra
S
Döpping
Sabine
S
Connert
Rolf
R
Gräbner
Rainer
R
Spanbroek
Birgit
B
Lemser
Michael
M
Beer
Markus
M
Hildner
Thomas
T
Hehlgans
Michael
M
van der Wall
Reina E
RE
Mebius
Agnes
A
Lovas
Gwendalyn J
GJ
Randolph
Falk
F
Weih
Andreas J R
AJ
Habenicht
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008221:Lymphoid Tissue / Q000166:cytology* / Q000502:physiology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha