- Open Access
Diverse roles of macrophage polarization in aortic aneurysm: destruction and repair
© The Author(s) 2018
- Received: 25 June 2018
- Accepted: 6 December 2018
- Published: 13 December 2018
Aortic aneurysm (AA) is defined as an enlargement of the aorta greater than 1.5 times its normal size. Early diagnosis of AA is challenging and mortality of AA is high. Curative pharmacological treatments for AA are still lacking, highlighting the need for better understanding of the underlying mechanisms of AA progression. Accumulating studies have proven that the polarization state of circulating monocyte-derived macrophages plays a crucial role in regulating the development of AA. Distinct macrophage subtypes display different functions. Several studies targeting macrophage polarization during AA formation and progression showed potential treatment effects. In this review, we focus on the recent advances of research on macrophage polarization in the progression of AA and propose that targeting macrophage polarization could hold great promise for preventing and treating AA.
- Macrophage polarization
- Aortic aneurysm
Aortic aneurysm (AA) is a dilatation of the aorta and is associated with severe complications, such as aortic rupture. Although significant progresses have been made in both open and endovascular surgery, curative pharmacological treatments for this condition, especially for inoperative small AA (diameter less than 5.5 cm) are still lacking [1–3]. The underlying mechanisms involved in the formation and progression of AA have not been fully elucidated but are increasingly recognized to involve chronic inflammatory response, extracellular matrix (ECM) degradation, and matrix metalloproteinase (MMP) upregulation. Various types of inflammatory cells, including dendritic cells, B cells, T cells, neutrophils, mast cells, and macrophages, have been identified in both human and experimental AA tissues and have been shown to be associated with increased levels of proinflammatory cytokines and diverse proteases that contribute to AA development [4–9]. Of them, macrophages have been demonstrated to play a critical role in the formation and progression of AA. The two major macrophage phenotypes are known as classically-activated M1 macrophages (proinflammatory phenotype) and alternative activated M2 macrophages (anti-inflammatory phenotype) [10–12]. The main characteristic of M1 macrophages is the production of proteolytic enzymes and pro-inflammatory cytokines, such as tumor necrosis factor (TNF), Interleukin 6 (IL-6), IL-12, IL-1β, nitric oxide synthase 2 (iNOS), Chemokine (C-X-C motif) ligand 9 (CXCL9) and the CXCL10. In contrast, M2 macrophages participate in the anti-inflammatory response through secretion of factors such as IL-10 or transforming growth factor-β (TGF-β) and are involved in ECM remodeling and tissue repair [10, 13]. Recent findings have shown distinct macrophage subsets present in human and experimental murine AA tissues and are known to have different functions in the progression of AA. In this review, we provide current knowledge of the roles of distinct macrophage subsets on the development of AA, and particularly highlight their potential translational applications.
AA is an asymptomatic but life-threatening aortic disease and constitutes the 13th most common cause of death in the U.S. In developing countries such as China, as the population ages and dietary pattern changes the morbidity of AA is gradually increasing. Along with the diagnostic imaging technology progresses, the diagnostic rate of AA is also increasing . In the current guidelines for AA treatment, for AA of diameter ≥ 5.5 cm, surgical resection, artificial vascular replacement or endoluminal stent repair are recommended. On the other hand, for small AA of diameter < 5.5 cm, the aortic dilation rate is slower, and the risk of aortic rupture is reduced; thus, traditional surgical treatment or endoluminal stent repair do not show obvious benefits. For patients with small AA, periodical imaging examinations to monitor the AA diameter are recommended; once the AA diameter reaches 5.5 cm or the dilatation rate of AA is higher than 0.5 cm per year, optional surgical repair or endoluminal stent repair would be considered. In summary, all current treatments for AA dependent on mechanical intervention. However, when most AAs are detected, they are below the threshold for repair, leading to a significant observation period during which there is currently no non-surgical therapy to prevent or slow AA expansion , highlighting a real need for better understanding of the potential mechanisms involved in the pathogenesis of AA.
Previous studies have shown that the main pathological features of AA include inflammatory cells infiltration, apoptosis of vascular smooth muscle cells (VSMCs), Upregulation of MMPs, and ECM degeneration. Inflammatory cells such as macrophages can infiltrate into aortic tissue and secrete MMPs and pro-inflammatory factors to promote destruction of ECM and induce apoptosis of VSMCs, resulting in AA formation. Studies have demonstrated that aortic injuries could induce the migration of bone marrow-derived cells to injury sites, where they differentiate into macrophages or fibroblasts, to participate in the immune response, repair and reconstruction of aortic wall [16, 17]. This phenomenon suggests that macrophages originating from bone marrow cells can function to repair the injured aortic tissues.
Numerous recent studies have suggested that M1 and M2 polarization of macrophages may be involved in the aortic remodeling and development of AA . Moore et al.  reported that hypertension in mice with angiotensin (Ang II) infusion is associated with accumulation of Ly6Chi monocytes in the aortic tissues. These cells differentiate into M2 macrophages, which likely promote ECM remodeling, including collagen deposition and elastin loss. Using laser capture microdissection (LCM) and immunohistochemistry, Boytard et al.  observed the distribution of subtypes of macrophages in human AA tissues. They found that M1 macrophages (CD68+MR−) were predominant in the adventitia, while M2 macrophages (CD68+MR+) were predominant in the intraluminal thrombus. They also found that stabilin 1, involved in the uptake and degradation of unwanted molecules, was overexpressed in M2 (CD68+MR+) macrophages, which suggested that M1 and M2 macrophages may play different roles in AA development. Hans et al.  reported that Notch1 haploinsufficiency prevents the influx of proinflammatory macrophages (M1) at the aneurysmal site by causing defects in macrophage migration and proliferation. Decreased levels of Notch1 protects against the formation of AA by preventing macrophage recruitment and attenuating the inflammatory response in the aorta. Hasan et al.  found that M1 and M2 macrophages are present in equal proportions in unruptured aneurysms. However, there is an increase in M1 macrophages and mast cells in ruptured aneurysms. A macrophage M1/M2 imbalance and upregulation of mast cells may play roles in the progression of cerebral aneurysms to rupture. Batra et al.  reported that IL (interleukin)-1β was differentially expressed in human plasma from patients with AA compared with matched atherosclerotic controls. Wang et al.  found that TNF-stimulated gene-6 (TSG-6) was elevated in both the plasma and aortic wall of patients with AA compared with healthy and risk-factor matched non-AA donors. Both IL-1β and TSG-6 are related with the regulation of macrophage polarization in AA. In our primary study, we observed that, at early stages of AngII induced AA in Apo E−/− mice, M1 macrophages were increased along with secretion of several pro-inflammatory cytokines and chemokines. After AA formation, M2 macrophages markedly increased along with secretion of anti-inflammatory cytokines and chemokines.
Macrophage subtypes involved in aortic remodeling and aneurysm
Ang II-infused ApoE−/− mice
M2 macrophage accumulation in the aortic wall
Moore et al. 
Human aneurysmal infrarenal aortic wall
M1 macrophage was predominant in the adventitia while the M2 macrophages in the intraluminal thrombus/stabilin 1
Boytard et al. 
Ang II-infused ApoE−/− mice
Hans et al. 
Macrophage M1/M2 imbalance and upregulation of mast cells
Hasan et al. 
Patients with AA
IL-1β was differentially expressed in human plasma with in patients with AA
Batra. et al. 
Patients with AA
NF-stimulated gene-6 (TSG-6) elevated in both the plasma and aortic wall of patients with AA
Wang et al. 
Macrophage polarization can regulate inflammation, thus affecting the development and prognosis of inflammation-related diseases. Recent studies have shown that using drugs or cell therapy modulating macrophage polarization could achieve therapeutic effects for AA [25–27]. Moran et al.  showed that systemic administration of the rapamycin inhibitor everolimus limits AA in the AngII-infused ApoE−/− mouse model via suppressed development of bone marrow CCR2 monocytes, reduced egress of these cells into the circulation and diminished IFNγ/lipopolysaccharide-stimulated M1 polarization in bone marrow monocyte-differentiated macrophages. In Yoshihara et al.  study, the AA model was developed by AngII infusion in ApoE−/− mice. AA formation and macrophage infiltration were significantly suppressed after Eicosapntemacnioc Acid (EPA) and Docosahexaenoic acid (DHA) administration. The expression of arginase 2, a marker of pro-inflammatory macrophages (M1), was significantly lower, and that of Ym1, a marker of anti-inflammatory macrophages (M2), was significantly higher after EPA and DHA administration. Pope et al.  reported that administration of D-series resolvins could attenuate murine AA formation by increasing M2 macrophage polarization and altering inflammatory cytokine expression. Dale et al.  showed that treatment of bone marrow-derived macrophages with Elastin-derived peptides (EDPs) could induce M1 macrophage polarization. Injection of M2-polarized macrophages reduced aortic dilation after aneurysm induction. EDPs promoted a pro-inflammatory environment in aortic tissues by inducing M1 polarization, and neutralization of EDPs attenuated aortic dilation. Andreata et al.  found that CD31 agonist P8RI induces the switching of M1macrophages to the reparative M2 phenotype and promotes the healing of experimental dissected aortas in Apo E−/− mice with Ang II infusion. Meng et al.  reported that adoptive transfer of Tregs dose-dependently prevented AngII-induced AA in ApoE−/− mice. One of the underlying mechanisms was that Tregs downregulated M1-related genes and upregulated M2-related genes, thus regulating macrophage polarization. Our group found that bone marrow derived mesenchymal stem cells (BM-MSCs) could regress the formation of AA by regulating macrophage polarization to restore the M1/M2 ratio and to reduce inflammation at the site of AA [30–32].
Macrophages polarization in the treatment of aortic aneurysm
AngII-induced AA in ApoE−/− mice
Bone marrow development of Ly6C + CCR2 + (inflammatory) monocytes
Decrease aortic dilatation
Moran et al. 
CaCl2 induced AA in C57BL/6 mice
Modulating M1/M2 macrophage polarization
Dale et al. 
Elastase-induced AA in C57/B6 mice
AngII-infused ApoE−/− mice
Increasing M2 macrophage polarization
Decrease in MMPs
Attenuated AA formation and progression
Pope et al. 
AngII-induced AA in ApoE−/− mice
Downregulated macrophage type 1–related genes and upregulated macrophage type 2–related genes
Declined proinflammatory cytokine expression and MMP-2 and MMP-9 levels and enhanced anti-inflammatory cytokine expression
Meng et al. 
AngII-induced AA in ApoE−/− mice
BM-MSC inhibited infiltration of M1 macrophages and preserved the construction of elastin
Decrease vascular inflammation
Prevent AA expansion
Yamawaki-Ogata et al. 
CaCl2 induced AA in C57BL/6 mice
TNF-α deletion but not IL-1β deletion, inhibited M1 macrophage polarization
Infusion of M1 polarized TNF-α−/− macrophages inhibited aortic diameter growth
Batra et al. 
CD31 agonist P8RI
AngII-induced AA in ApoE−/− mice
CD31 signaling promotes the switching of proinflammatory macrophages to the reparative phenotype
Promoting the resolution of intramural hematoma and the production of collagen in dissected aortas
Andreata et al. 
EPA and DHA
AngII-induced AA in ApoE−/− mice
Promote macrophage polarization toward the M2 phenotype
Inhibited aortic inflammation, degeneration and macrophage infiltration
Yoshihara et al. 
In the present review, we summarized recently published studies on the roles of macrophage polarization in the aortic remodeling and development of AA. We highlighted the functions of macrophage subsets, which are complex, and could be either destructive or reparative during AA development. M1 macrophages accumulate in the aortic wall and dominate the cellular milieu and mainly clear cellular debris at early stage of AA. Thereafter, M1 macrophages secrete inflammatory cytokines that affect the consequent phases of aortic remodeling and initiate aortic tissue repair coordinated by M2 macrophages. The prolonged effects of M1 macrophages extend the destructive effects of inflammatory responses and cause expansion of AA. More recently, studies targeting macrophage differentiation towards the M2 phenotype have been shown to promote the resolution of aortic inflammation and slow AA progression. Modulation of macrophage subset polarization is believed to be an attractive strategy to prevent the progression of AA. However, macrophage polarization phenotypes are not always mutually exclusive, and it still remains unsolved whether some functional subsets represent real distinct populations. Additionally, the molecular and cellular mechanisms underlying regulation of macrophage polarization during AA development are complex and multifactorial. Further studies with more animal models and patients will be needed to be conducted to determine the precise roles of macrophage polarization in AA in order to develop effective treatment and prevention strategies.
ZC and XF have been involved in writing, compiling the manuscript. YZ, YW, QW and XL contributed significantly on literature and critical suggestions to reshape the manuscript. XF and XZ conceived the concept of this review, and revised it critically for publication standards. All authors read and approved the final version of manuscript.
The authors would like to thank Professor Hengyi Xiao (West China School of Mdicine/West China Hospital, Sichuan University, P.R.China) and Professor Guang-sen Zhang (Department of Hematology, Institute of Molecular Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan, P.R. China) for their kindly support in this study.
Zhao Cheng—First Author.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analysed during this study are included in this published article.
Consent for publication
Ethics approval and consent to participate
This study was carried out in strict accordance with recommendations of the Regulations on human and animal experimentation of Central South University (China).
This work was financially supported by the National Natural Science Foundation of China (Grant No. 81400343), National Natural Science Foundation of China (Grant No. 81400093), & Natural Science Foundation of Hunan Province, China (Grant No. 2018JJ3757).
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