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Metalloproteinase production from macrophages – a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction
Author(s) -
Newby Andrew C.
Publication year - 2016
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/ep085567
Subject(s) - matrix metalloproteinase , inflammation , macrophage , microbiology and biotechnology , tumor necrosis factor alpha , immunology , downregulation and upregulation , monocyte , cancer research , medicine , biology , biochemistry , gene , in vitro
New FindingsWhat is the topic of this review? The review discusses how in atherosclerotic plaques, a combination of inflammatory mediators together with loss of anti inflammatory factors is most likely to be responsible for the excess of MMP over TIMP expression that causes plaque rupture and myocardial infarction.What advances does it highlight? Regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) is divergent between human and mouse macrophages. There is prostaglandin E 2 ‐dependent and ‐independent regulation. Inflammatory cytokines act through distinct (albeit overlapping) signalling pathways to elicit different patterns of MMP and TIMP expression. Transcriptional and epigenetic regulation occurs.Matrix metalloproteinases (MMPs) produced from macrophages contribute to plaque rupture, atherothrombosis and myocardial infarction. New treatments could emerge from defining the mediators and underlying mechanisms. In human monocytes, prostaglandin E 2 (PGE 2 ) stimulates MMP production, and inflammatory mediators such as tumour necrosis factor α, interleukin‐1 and Toll‐like receptor ligands can act either through or independently of PGE 2 . Differentiation of human monocytes to non‐foamy macrophages increases constitutive expression of MMP‐7, ‐8, ‐9, ‐14 and ‐19 and tissue inhibitor of MMP (TIMP)‐1 to ‐3 through unknown, PGE 2 ‐independent mechanisms. Human macrophages express more MMP‐1, ‐7 and ‐9 and TIMP‐3 and less MMP‐12 and ‐13 than mouse macrophages. Inflammatory mediators working through activator protein‐1 and nuclear factor‐κB transcription factor pathways upregulate MMP‐1, ‐3, ‐10, ‐12 and ‐14 in human macrophages (MMP‐9, ‐12 and ‐13 in mice), and studies with plaque tissue sections and isolated foam cells confirm this conclusion in vivo . Classical activation with granulocyte–macrophage colony‐stimulating factor upregulates MMP‐12, whereas interferon‐γ upregulates MMP‐12, ‐14 and ‐25 and downregulates TIMP‐3 in human but not mouse macrophages. Alternative activation with interleukin‐4 markedly stimulates the expression of only MMP‐12 in humans and MMP‐19 in mice. The anti‐inflammatory cytokines interleukin‐10 and transforming growth factor‐β decrease production of several MMPs. Epigenetic upregulation of MMP‐14 during foam cell formation or by granulocyte–macrophage colony‐stimulating factor occurs by decreasing miRNA‐24. A ‘perfect storm’ caused by a combination of these mechanisms is most likely to promote MMP‐mediated macrophage invasion, tissue destruction and atherosclerotic plaque rupture.