Roles of Immunity and Metabolism in Aortic Dissection: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Wenhui He.

Aortic dissection (AD) is a cardiovascular disease that seriously endangers the lives of patients. The mortality rate of this disease is high, and the incidence is increasing annually, but the pathogenesis of AD is complicated. In recent years, an increasing number of studies have shown that immune cell infiltration in the media and adventitia of the aorta is a novel hallmark of AD. These cells contribute to changes in the immune microenvironment, which can affect their own metabolism and that of parenchymal cells in the aortic wall, which are essential factors that induce degeneration and remodeling of the vascular wall and play important roles in the formation and development of AD.

  • aortic dissection
  • immunity
  • metabolism

1. Introduction

Aortic dissection (AD) is a dangerous cardiovascular disease. The incidence rate in the general population is 3–5 cases/100,000 persons, and the incidence rate in the middle-aged and elderly population can be as high as 10 cases/100,000 persons. The mortality rate of untreated type A acute AD (AAD) patients after symptom onset is 1% to 2% per hour [1,2,3,4][1][2][3][4]. Without clinical intervention, the mortality rate is as high as 50% within 48 h after onset. The long-term survival of patients who survive an acute aortic event is reduced, with an increased risk of death that extends to 90 days from diagnosis [5,6][5][6]. The aortic wall is composed of the intima, media and adventitia from the inside to the outside. The inner membrane is composed of endothelial cells (ECs) and the subendothelial layer. The media is mainly composed of elastic fibers, collagen fibers and vascular smooth muscle cells (VSMCs). The adventitia of the aorta is composed of loose connective tissue, which contains elastic fibers, collagen fibers and fibroblasts. Under physiological conditions, the three aortic membranes stick closely to each other and jointly bear the pressure of blood flow in the blood vessels. However, when there is a break in the inner membrane, the impact of blood can further tear and expand the gap, causing the three-layer membrane to separate and resulting in the formation of AD. The pathogenesis of AD is not completely clear.
Apart from genetics, lifestyle habits and background diseases, it is important to focus on the cellular and molecular mechanisms of AD, and abnormal immunity and metabolism are two essential aspects involved in AD initiation and progression [11,12,13][7][8][9]. Recent clinical and basic studies have shown that extravascular matrix degradation and VSMC apoptosis are exacerbated as the degree of inflammation increases [14,15][10][11]. This finding suggests that the inflammatory response may play an important role in the early onset of AD and can activate multiple pathological processes to further promote the onset of AD.

2. Immunity in AD

2.1. Innate Immunity and Associated Signaling in AD

2.1.1. Neutrophils

Neutrophils have phagocytic and chemotactic functions and play a role in the inflammatory cascade after AAD. Lauren et al. showed that neutrophil infiltration into the adventitia occurred within 12 h after AD and peaked from 12 to 24 h [23][12]. Moreover, clinical studies have shown that the neutrophil-to-lymphocyte ratio (NLR) can be used as a prognostic predictor of AD [24,25][13][14]. Apart from this, neutrophils are the main cells that secrete MMPs. Some researchers have shown that the accumulation of MMP-9 leads to disorders of ECM metabolism, promoting inflammation and the degradation of elastic fibers and accelerating the expansion and rupture of the dissection [26][15].

2.1.2. Monocytes

Monocytes are a heterogeneous cell population that can be categorized into three subpopulations with different phenotypic and functional properties: “classical” (CD14++CD16−), “intermediate” (CD14++CD16+) and “nonclassical” (CD14+CD16+). Furthermore, classical monocytes are significantly increased, whereas intermediate monocytes are significantly decreased in AAD [34][16]. Factors such as oxidative stress, cytokines, viral or bacterial infections, high blood sugar or high low-density lipoprotein (LDL) levels can activate the vascular endothelium, induce monocyte recruitment, promote the secretion of the chemokines CCL2, CCL5 and CCL7 and upregulate adhesion molecules such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which can promote the rolling of circulating blood mononuclear cells, adhesion to ECs and migration into the tissue [35,36][17][18]. Monocytes that migrate from the blood to the tissues play a phagocytic role, produce inflammatory factors and then differentiate into tissue macrophages and dendritic cells [37,38][19][20]. It has been reported that IL-6 can induce monocytes to differentiate into macrophages and can mediate Th17 production through the IL-6 signal transducer and activator of transcription 3 (STAT3) pathway [39][21]. Activated monocytes and platelet receptor glycoprotein Ib alpha (GPIbα) participate in local thrombin amplification through coagulation factor XI (FXI), thereby promoting the development of vascular inflammation and hypertension and accelerating the progression of AD [40][22].

2.1.3. Macrophages

Pathophysiological processes, including macrophage migration and infiltration into the aorta, differentiation or phenotype transformation, the secretion of various inflammatory factors and the release of extracellular matrix (ECM)-degrading proteins, are closely related to the occurrence and development of AD [42][23]. Inflammatory factors in the peripheral blood and vascular wall of patients with Stanford type A dissection were examined by Del Porto et al., and the results showed that macrophages were the main inflammatory cells that infiltrated aortic tissues, the ECM was degraded, and the immune response played an important role in this process [43][24].

2.1.4. Mast Cells

Mast cells promote the development and progression of AD through the release of inflammatory factors. Gao et al. found that mast cells could secrete the proinflammatory factors interferon-γ (IFN-γ) and MMPs, which cause VSMC apoptosis and vascular remodeling, leading to the formation of AA [51][25]. In addition, Springer et al. showed that in vivo mast cells could partially and transiently regulate systemic IL-6 homeostasis [52][26].

2.2. Adaptive Immunity and Associated Signaling in AD

2.2.1. T Cells/Th Cells

T cells/Th cells have been shown to induce VSMC apoptosis and MMP synthesis [54][27], which suggests that these cells play a role in the development of AD [55,56][28][29]. Clinical studies have shown high levels of CD3+, CD4+, CD8+ and CD45+ T cells in the aortic tissue of AD patients, indicating that T cell activation is involved in the development of AD [57][30]. CD4+ T cells can differentiate into different subpopulations under different conditions, such as T helper 1 (Th1), Th2, Th17 and T regulatory (Treg) cells [58][31].

2.2.2. B Cells

B cells play a key role in adaptive immunity and participate in the pathogenesis of AD, mainly through their ability to detect and process antigens [66,67][32][33]. Saraff et al. revealed that in an angiotensin II (Ang II)-induced AD model, B cells mainly infiltrated the media of the vessel wall. During AD development, B cells are stimulated by antigens to proliferate and differentiate into plasma cells, which synthesize and secrete antibodies and circulate in the blood to perform humoral immune functions. However, the specific role of B cells in AD is still unclear.

2.3. Interactions of Immune Cells in AD

Local inflammatory responses and systemic inflammatory responses in the vessel wall are triggered after AD occurs; this process involves interactions among immune cells. The high expression of chemokines and granulocyte colony-stimulating factor in AD tissue after local inflammation leads to neutrophil infiltration and accelerates the occurrence of lesions in the aortic media [70][34]. NETs facilitate the secretion of inflammatory factors by macrophages and indirectly activate Th17 cells to promote inflammation [71][35]. Furthermore, among inflammatory factors, IL-6 can induce the differentiation of monocytes into macrophages and mediate the production of Th17 through the IL-6–STAT3 pathway; Th17 cells can promote the chemotaxis, adhesion and migration of monocytes by mediating inflammatory responses [72][36]; IL-8 has a role in regulating neutrophil mobilization and migration [73][37]; IL-1β can promote the secretion of MMPs by immune cells through the phosphorylation of p38 [74][38]; and exosomes from monocytes are transformed into active macrophages through the NF-κB signaling pathway which continue to secrete a variety of inflammatory substances, proteolytic enzymes and ECM-degrading proteins and continue to damage blood vessels [75][39]. In addition, immune cells cause changes in the microenvironment, such as the accumulation of homocysteine (Hcy).

3. Metabolisms in AD

3.1. Carbohydrate Metabolism

Glucose is an essential source of energy for metabolism. Under normal oxygen conditions, cells prefer glycolysis to the oxidative phosphorylation (OXPHOX) process, known as “Warburg effect”. Lactic acid accumulation and OXPHOX damage caused by the Warburg effect are common in parenchymal cells in AD [78,79][40][41]. The inflammatory tissue of AD is often hypoxic [80,81][42][43]. Under this condition, the expression of hypoxia-inducible factor (HIF), especially O2-sensitive HIF-1α, is enhanced, which plays an important role in the Warburg effect [82,83,84][44][45][46]. Migrating VSMCs have increased glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression to promote glycolysis [85,86][47][48]. Lactate dehydrogenase (LDHA) is also upregulated, stimulating VSMC proliferation, migration and synthetic phenotypic transformation. In vivo, the inhibitor of LDH and lactate reduced the degradation of elastic fibers, collagen deposition and MMP2/9 production and inhibited the phenotypic transformation of VSMC so that the progression of AD was delayed [87,88][49][50]. The NR1D1–ACO2 axis interferes with aberrant tricarboxylic acid (TCA) cycle functions. α-KG, the substrate of ACO2, supplementation is regarded as an effective therapeutic approach for AD which can increase mitochondrial ETC complex expression to prevent AAA formation [89][51]. Hypoxic conditions cause a shift in glucose flux towards the pentose phosphate pathway (PPP). High levels of NADPH generated via the PPP as part of an antioxidant mechanism protect VSMCs from apoptosis [90][52].

3.2. Lipid Metabolism

It is becoming increasingly clear that high lipid levels predispose individuals to the development of clinical cardiovascular diseases. When the β oxidation of fatty acids (FAs) is suppressed, less acetyl coenzyme A (acetyl-CoA) enters the TCA, thereby inhibiting OXPHOX [92][53]. Increased concentrations of non-esterified FAs induce endoplasmic reticulum stress, mitochondrial dysfunction, inflammation and cytokine release, which are causative factors of AD [93][54]. Observational studies found obvious dyslipidemia in AD patients, and the in-hospital mortality of AD patients was correlated with dyslipidemia [94][55]. The secretion of arachidonic acid (ARA) and increased synthesis of prostaglandin E2 (PGE2) are associated with endothelial dysfunction and vascular inflammation in patients with MFS [95,96][56][57].

3.3. Amino Acid Metabolism

Aberrant and dysregulated signaling associated with amino acid metabolism is closely implicated in AD. Wang et al. showed that plasma aminograms were significantly altered in patients with AD [102][58]. According to epidemiological studies, hyperhomocysteinemia (HHcy) is a hallmark of vascular injury. HHcy stimulates the secretion of IL-6 and MCP-1 and the subsequent recruitment of monocytes/macrophages and promotes adventitial fibroblasts’ transformation into myofibroblasts [103][59]. Vitamin B restored TGF-β signaling and promoted lysyl-oxidase-mediated collagen maturation in aortic media. Vitamin B can serve as a synergistic drug for the treatment of MFS [104][60]. S-adenosyl-L-homocysteine cysteine (SAH) is a more sensitive biomarker of cardiovascular disease than Hcy. High levels of SAH in plasma contribute to endothelial dysfunction [105][61]. Overexpression of solute carrier family 1 member 5 (SLC1A5), a key glutamine (GLN) transporter, results in mTORC1 activation and VSMC proliferation; these changes are attenuated after additional treatments with GLN metabolism inhibitor BPTES [106,107][62][63]. Gallina found that AMPA-type glutamate receptors mediate VSMC transformation into the contractile phenotype [108][64]

3.4. Interconnection and Cross-Regulation of Metabolism in AD

The metabolism of carbohydrates, lipids and amino acids is linked through a common intermediate product (acetyl-CoA) and a common metabolic pathway, the TCA cycle, to form a whole system; therefore, when there is a metabolic disorder in any one or more of these factors, there is crosstalk with other pathway disorders. The Warburg effect is not only associated with the glycolytic pathway; “errors” in the glycolytic pathway can bring about “mistakes” in amino acid and lipid metabolism. This series of changes promotes the production of ROS, NADPH and NO, and the production of these substances results in various adverse consequences through various pathways, such as parenchymal cell disruption and dysfunction and the activation of inflammatory factors and inflammasomes. These adverse consequences can eventually promote the occurrence and development of AD.

4. Synergism or Antagonism between Immunity and Metabolism in AD

4.1. Metabolism Shapes the Immune Microenvironment of AD

Immune cells and parenchymal cells need to constantly regulate their own metabolism to perform their corresponding functions in AD. During this process, the production of both cytokines and metabolites alters the microenvironment, further affecting metabolism; for example, the preferential production of lactate via the Warburg effect promotes neutrophil activity [113][65]. Nox-derived ROS, which are maintained by NADPH produced via the PPP, can effectively induce the formation of NETs [114,115][66][67]. The production of α-KG via GLN catabolism for Jmjd3-dependent epigenetic reprogramming is important for alternative activation of M2 macrophages [116][68]. Lipoprotein a (Lp(a)) mediates a proinflammatory response through oxidized phospholipid (OxPL), which is recognized as a danger-associated molecular pattern by pattern recognition receptors on innate immune cells and induces monocyte trafficking to induce inflammation in the arterial wall [117][69].

4.2. Regulatory Effects of Immune Cells on Metabolic Reprogramming in AD Parenchymal Cells

Different immune cell subpopulations differentiate due to metabolic disorders and, in turn, regulate the metabolic reprogramming of parenchymal cells [122][70]. When AD is accompanied by inflammation, disturbed carbohydrate, lipid and amino acid metabolism in immune cells results in oxidative stress, mitochondrial stress and endoplasmic reticulum stress, and these series of changes prompt cells to produce ROS, NADPH and NO and activate inflammatory vesicles, accelerating EC, VSMC and other parenchymal cell migration and apoptosis, as well as enhancing ECM degradation [123,124,125,126][71][72][73][74]. Lian et al. revealed that macrophages induced HIF-1α activation in response to fumarate accumulation, which triggers vascular inflammation, metalloproteinase degradation and elastic plate rupture through increased deintegrin and extracellular mesenchymal protein structural domain 17 (ADAM17) expression in humans and mouse models [127,128][75][76]. The researchers also identified an enzyme secreted by inflammatory cells called FLp-PLA2, which can hydrolyze glycerophospholipids to produce bioactive lipids, leading to vascular endothelial dysfunction and exacerbating vascular inflammation, and is clinically regarded as an early warning indicator of AD [129,130][77][78]. Additionally, in M1-type macrophages, interruption of the TCA cycle causes the accumulation of the intermediate product succinate, which enhances the inflammatory response and further regulates metabolic reprogramming in parenchymal cells [112][79]. In addition, ox-LDL can promote the glycolytic capacity of macrophages, thereby promoting cholesterol uptake by VSMCs. Cholesterol can regulate Nox isoforms and redox signaling in VSMCs to provoke vascular disease [131][80].

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