Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection

In this 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 upregulated 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 downregulated in IL-3 deficient aortas. Mechanistically, we found recombination 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.

Source: Clinical Science - March 9, 2018 Category: Biomedical Science Authors: Liu, C., Zhang, C., Jia, L., Chen, B., Liu, L., Sun, J., Zhang, W., You, B., Li, Y., Li, P., Du, J. Tags: PublishAheadOfPrint Source Type: research