Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin β-receptor NF-κB Signaling

Katharina Lötzer, Sandra Döpping, Sabine Connert, Rolf Gräbner, Rainer Spanbroek, Birgit Lemser, Michael Beer, Markus Hildner, Thomas Hehlgans, Michael Van Der Wall, Reina E. Mebius, Agnes Lovas, Gwendalyn J. Randolph, Falk Weih, Andreas J.R. Habenicht

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Objective-Mouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin β-receptor (LTβR). Circumstantial evidence has linked the SMC LTβR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTβR signaling in cultured SMC. Methods and Results-TNFR-1 signaling activated the classical RelA NF-κB pathway, whereas LTβR signaling activated the classical RelA and alternative RelB NF-κB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB. Microarrays showed that simultaneous TNFR-1/LTβR 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/LTβR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTβR-activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr SMC indicated that LTβR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype. Conclusion-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.

Original languageEnglish
Pages (from-to)395-402
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

Keywords

  • Chemokines
  • Immune response
  • Lymphotoxin-β receptor
  • Signaling pathways
  • Smooth muscle cells
  • Tumor necrosis factor receptor

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    Lötzer, K., Döpping, S., Connert, S., Gräbner, R., Spanbroek, R., Lemser, B., Beer, M., Hildner, M., Hehlgans, T., Van Der Wall, M., Mebius, R. E., Lovas, A., Randolph, G. J., Weih, F., & Habenicht, A. J. R. (2010). Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin β-receptor NF-κB Signaling. Arteriosclerosis, thrombosis, and vascular biology, 30(3), 395-402. https://doi.org/10.1161/ATVBAHA.109.191395