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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 23, 2009 |
| Title |
Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizers upon combined TNFR1/LTBR NF-kB signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin ß receptor (LTßR). Circumstantial evidence has linked the SMC LTßR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTßR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-κB pathway, whereas LTßR signaling by agonistic anti LTßR antibody activated both the classical RelA and alternative RelB NF-κB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTßR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTßR-RelB activation component of NF-κB signaling was obligatory to generate the LTO phenotype. TNFR1-LTßR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTßR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy.
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| Overall design |
Smooth muscle cells in tissue culture were stimulated with agonists and subsequently microarray, RT-PCR, and protein assays / analyses were performed
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| Contributor(s) |
Lötzer K, Beer M, Habenicht A |
| Citation(s) |
20139367, 20139359 |
| Submission date |
Mar 02, 2009 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Andreas Johann Richard Habenicht |
| E-mail(s) |
Andreas.habenicht@med.uni-muenchen.de
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| Organization name |
Ludwig Maximilians Universität München
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| Department |
Medicine
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| Lab |
Institute for Cardiovascular Disease Prevention
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| Street address |
Pettenkoferstraße 9a
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| City |
Munich |
| State/province |
Bavaria |
| ZIP/Postal code |
80336 |
| Country |
Germany |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA114833 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE15062_RAW.tar |
84.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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