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Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection
Satoko Ohno-Urabe1, Hiroki Aoki2, Michihide Nishihara1
1Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
Background:
Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD.
Methods And Results:
We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction.
Conclusions:
These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.
Insights
Macrophage Socs3 is crucial for preventing aortic dissection (AD) by promoting healing after initial aortic rupture. Its absence leads to inflammation and tissue destruction, progressing to AD.
Area of Science:
- Cardiovascular Biology
- Immunology
- Pathogenesis of Aortic Dissection
Background:
- Aortic dissection (AD) is a critical condition involving aortic wall damage.
- Interleukin-6 (IL-6) is implicated in AD pathogenesis.
- This study explores the role of signal transducer and activator of transcription 3 (STAT3) signaling, a downstream IL-6 pathway in macrophages, in AD.
Purpose of the Study:
- To investigate the role of STAT3 signaling in macrophages in the pathogenesis of aortic dissection.
- To elucidate the molecular mechanisms underlying the development of AD following aortic stress.
Main Methods:
- Aortic stress was induced in mice using angiotensin II infusion and infrarenal aorta stiffening.
- Macrophage-specific deletion of the Suppressor of Cytokine Signaling 3 (Socs3) gene was performed in knockout (KO) mice.
- Pathological and molecular changes were analyzed in wild-type (WT) and mSocs3-KO mice, alongside human AD samples.
Main Results:
- Focal medial rupture occurred in WT and mSocs3-KO mice but healed in WT mice.
- Rupture progressed to AD in mSocs3-KO mice, characterized by premature cell proliferation, inflammation, and tissue-destructive macrophage phenotypes.
- Aberrant smooth muscle cell modulation and TGF-β signaling were observed in mSocs3-KO mice; STAT3 activation was found in human AD adventitial macrophages.
Conclusions:
- Macrophage Socs3 is essential for regulating inflammatory responses and smooth muscle cell differentiation, promoting fibrotic healing and preventing AD.
- The study highlights a sequence of events preceding AD, involving focal medial rupture and the critical role of macrophage Socs3 in healing.
- Understanding these mechanisms can aid in predicting and preventing AD development and progression.
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