Thoracic aortic aneurysm and dissection (TAAD) is due to degeneration of the aorta and causes a high mortality rate, while molecular mechanisms for the development of TAAD are still not completely understood. In the present study, 3-aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were up-regulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly down-regulated in IL-3 deficient aortas. Mechanistically, we found recombinant IL-3 could increase MMP12 production and activity from macrophages in vitro. Silencing of IL-3 receptor β, which was mainly expressed in macrophages but not SMCs, diminished the activation of c-Jun N terminal kinase (JNK)/extracellular-regulated protein kinases 1/2 (ERK1/2)/AP-1 signals, and decreased MMP12 expression in IL-3 stimulated macrophages. Moreover, both circulating and aortic inflammation were decreased in IL-3 deficient aortas. Taken together, our results demonstrated that IL-3 stimulated the production of MMP12 from macrophages by a JNK- and ERK1/2-dependent AP-1 pathway, contributing to TAAD formation. Thus, the IL-3/IL-3Rβ/MMP12 signals activation may be an important pathological mechanism for progression of TAAD.
Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection
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Chang Liu, Congcong Zhang, Lixin Jia, Boya Chen, Luxin Liu, Jie Sun, Wenmei Zhang, Bin You, Yulin Li, Ping Li, Jie Du; Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection. Clin Sci (Lond) 30 March 2018; 132 (6): 655–668. doi: https://doi.org/10.1042/CS20171529
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