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

Mar 11, 2018Clinical science (London, England : 1979)

Interleukin-3 increases enzyme production in immune cells that may promote chest artery bulges and tears

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Abstract

The expression levels of genes linked to the interleukin-3 (IL-3) signaling pathway were found to be up-regulated during thoracic aortic aneurysm and dissection (TAAD) development in a mouse model.

IL-3 positive cells were notably increased in the aortas of TAAD mice, particularly among smooth muscle cells.
Deficiency of IL-3 resulted in a reduction of TAAD formation induced by 3-aminopropionitrile (BAPN).
Matrix metalloproteinase 12 (MMP12) expression was significantly down-regulated in IL-3 deficient aortas compared to wild-type.
Recombinant IL-3 was shown to enhance MMP12 production and activity from macrophages.
Silencing of the IL-3 receptor β in macrophages led to decreased activation of specific signaling pathways and reduced MMP12 expression.
Both circulating and aortic inflammation levels were lower in IL-3 deficient aortas.

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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 macrophagesSilencing 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. in vitro

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

Abstract

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