Article: Complexity of Inflammation in the Trajectory of Vascular Disease: Interleukin 6 and Beyond.
2023 Volume 16, Issue 1, Page(s) 8–16
Abstract: Takayasu's arteritis, first described by Dr. Mikito Takayasu in 1908, is a systemic vasculitis that mostly affects the aorta and its major branches. Although the etiology of the disease is yet unknown, genetic and environmental factors may both play a ... ...
| Abstract | Takayasu's arteritis, first described by Dr. Mikito Takayasu in 1908, is a systemic vasculitis that mostly affects the aorta and its major branches. Although the etiology of the disease is yet unknown, genetic and environmental factors may both play a role. One hundred years after the discovery of Takayasu's arteritis, inflammation is finally widely recognized as a fundamental condition common to all vascular diseases, and clinical trials have proven the efficacy of molecularly targeted drugs that block each step of the NLRP3 inflammasome/interleukin (IL)-1β/IL-6 cascade in patients with atherosclerotic vascular disease and elevated C-reactive protein (CRP). Recent advances have also been made in the treatment of Takayasu's arteritis. The randomized controlled trials and subsequent open-label and post-marketing surveillance studies in Japan have demonstrated that tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of Takayasu's arteritis and prevents relapse during tapering of prednisolone doses. IL-6 is also heavily engaged in the remodeling of large vessels after acute aortic dissection as demonstrated in animal studies. In patients with acute aortic dissection, those with markedly elevated CRP levels in the acute phase are known to have an increased risk of aorta-related events, such as rupture due to aortic diameter enlargement, in the subacute and chronic phases. We discovered that elevated CRP levels following aortic dissection are caused by IL-6, which is produced by neutrophils that infiltrate the adventitia of the dissected aorta. In a mouse model of acute aortic dissection, we showed that IL-6 produced by these neutrophils causes progressive destruction of the arterial wall structure and that blockade of IL-6 signaling can prevent post-dissection vascular remodeling and improve life outcome. Therefore, inhibiting IL-6 signaling is anticipated to be effective in the secondary prevention of myocardial infarction and suppression of vascular modeling after dissection and even as an anti-inflammatory therapy for Takayasu's arteritis; however, this approach does not solve everything. Undoubtedly, the mechanisms of inflammation in vascular disease are diverse and complex, and the cytokines and cell populations involved at each site (coronary artery vs. aorta) and in each phenotype (atherosclerosis vs. aortic aneurysm vs. aortic dissection) need to be understood for each type of inflammation. Osteopontin (OPN) is a recruiter of monocytes and macrophages, induces cellular immune responses as a Th1 cytokine, acts as a fibrosis-promoting factor, and has been shown to be deeply involved in the pathogenesis of vascular diseases. We have shown that senescent T cells, which emerge with obesity and aging, secrete significant amounts of OPN, leading to metabolic abnormalities and chronic inflammation. Neutrophil extracellular traps (NETs) released from activated neutrophils have been shown to contribute to the pathogenesis of acute coronary syndromes (ACS) by interacting with macrophages, platelets, and vascular endothelial cells and thus promoting plaque erosion and immunothrombosis. In addition to standard anticoagulant and antiplatelet therapies, the effectiveness of anti-immunothrombotic therapies targeting NETs as a new preventive and therapeutic approach for ACS will be examined in the future. |
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| Language | English |
| Publishing date | 2023-03-10 |
| Publishing country | Japan |
| Document type | Journal Article |
| ZDB-ID | 2394256-3 |
| ISSN | 1881-6428 ; 1881-641X |
| ISSN (online) | 1881-6428 |
| ISSN | 1881-641X |
| DOI | 10.3400/avd.ra.23-00003 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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