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Plasmin triggers cytokine induction in human monocyte-derived macrophages
Qun Li1, Yves Laumonnier, Tatiana Syrovets
1Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstr. 20, D-89081 Ulm, Germany.
Objective:
Fibrinolytic activity is upregulated in atherosclerotic lesions, yet little is known about the role of plasmin in macrophage function. We postulated a direct effect of plasmin on human monocyte-derived macrophages.
Methods And Results:
Plasmin activates macrophages via the annexin A2 heterotetramer composed of annexin A2 and S100A10 with subsequent stimulation of Janus kinase JAK1/TYK2 signaling. JAK1/TYK2 leads to STAT3 activation, Akt-dependent NF-kappaB activation, and phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen-activated kinase p38. These signaling pathways trigger nuclear translocation of STAT3 and p65 transcription factors and the induction of the proinflammatory cytokines tumor necrosis factor-alpha and IL-6. Inhibitors of JAK, p38, and NF-kappaB revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor-alpha and IL-6 induction. By contrast, the extracellular signal-regulated kinase 1/2 activation is essential only for the IL-6 expression. The activation clearly depends on the proteolytic activity of plasmin, which cleaves the A2 subunit of the annexin A2 heterotetramer. Downregulation of each of the receptor subunits by antisense oligodeoxynucleotides abolished the plasmin-induced expression of proinflammatory cytokines stressing the crucial role the annexin A2 heterotetramer.
Conclusions:
Plasmin generated at sites of inflammation such as atherosclerotic lesions will trigger cytokine expression in human macrophages.
Insights
Plasmin activates macrophages by binding to the annexin A2 heterotetramer, initiating signaling pathways that induce pro-inflammatory cytokine production, crucial for understanding inflammation in conditions like atherosclerosis.
Area of Science:
- Immunology
- Vascular Biology
- Molecular Medicine
Background:
- Fibrinolytic activity, involving plasmin, is elevated in atherosclerotic lesions.
- The specific role of plasmin in macrophage function within these lesions remains largely unexplored.
Purpose of the Study:
- To investigate the direct impact of plasmin on human monocyte-derived macrophages.
- To elucidate the molecular mechanisms underlying plasmin-mediated macrophage activation.
Main Methods:
- Utilized human monocyte-derived macrophages.
- Investigated signaling pathways including JAK/STAT, Akt/NF-kappaB, and MAPK.
- Employed inhibitors and antisense oligodeoxynucleotides to probe pathway dependency.
Main Results:
- Plasmin activates macrophages via the annexin A2 heterotetramer (annexin A2/S100A10).
- This activation triggers JAK1/TYK2, STAT3, NF-kappaB, ERK1/2, and p38 signaling.
- Plasmin-induced cytokine (TNF-α, IL-6) expression is dependent on annexin A2 heterotetramer and specific signaling pathways.
Conclusions:
- Plasmin generated at inflammatory sites, such as atherosclerotic lesions, stimulates cytokine expression in human macrophages.
- This highlights a novel role for plasmin in modulating the inflammatory response within atherosclerosis.
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