Regulation of efferocytosis by caspase-dependent apoptotic cell death in atherosclerosis

International Journal of Biochemistry and Cell Biology 120 (2020) 105684

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Regulation of efferocytosis by caspase-dependent apoptotic cell death in atherosclerosis

T

Amir Tajbakhsha,b, Petri T. Kovanenc, Mahdi Rezaeed, Maciej Banache,f, Seyed Adel Moallemg,h, Amirhossein Sahebkari,j,k,* a

Halal Research Center of IRI, FDA, Tehran, Iran Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran c Wihuri Research Institute, Helsinki, Finland d Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran e Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland f Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland g Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran h Department of Pharmacology and Toxicology, School of Pharmacy, Al-Zahraa University, Karbala, Iraq i Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran j Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran k School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b

A R T I C LE I N FO

A B S T R A C T

Keywords: Apoptosis Atherosclerosis Necrosis Phagocytic cells Plaque rupture Reactive oxygen species

During the growing process of the atherosclerotic lesions, lipid-filled macrophage foam cells form, accumulate, and ultimately undergo apoptotic death. If the apoptotic foam cells are not timely removed, they may undergo secondary necrosis, and form a necrotic lipid core which renders the plaque unstable and susceptible to rupture. Therefore, the non-lipid-filled fellow macrophages, as the main phagocytic cells in atherosclerotic lesions, need to effectively remove the apoptotic foam cells. In general, in apoptotic macrophages, caspases are the central regulators of several key processes required for their efficient efferocytosis. The processes include the generation of “Find-Me” signals (such as adenosine triphosphate/uridine triphosphate, fractalkine, lysophosphatidylcholine, and sphingosine-1-phosphate) for the recruitment of viable macrophages, generation of the "Eat-Me" signals (for example, phosphatidylserine) for the engulfment process, and, finally, release of anti-inflammatory mediators (including transforming factor β and interleukin-10) as a tolerance-enhancing and an anti-inflammatory response, and for the motile behavior of the apoptotic cell. The caspase-dependent mechanisms are operative also in apoptotic macrophages driving the atherogenesis. In this review, we explore the role of the molecular pathways related to the caspase-dependent events in efferocytosis in the context of atherosclerosis. Understanding of the molecular mechanisms of apoptotic cell death in atherosclerotic lesions is essential when searching for new leads to treat atherosclerosis.

1. Introduction Atherosclerosis is a chronic and progressive disease of the arterial wall that is prompted via lipid accumulation in the arterial inner layer, the intima, and that is strongly associated with macrophage-mediated inflammation (Back et al., 2019). Moreover, it has been shown that macrophage-mediated inflammation is regulated by macrophage clearance of apoptotic cells (ACs), efferocytosis (Fig. 1) (Tajbakhsh et al., 2019a, b; Tajbakhsh et al., 2018).

The continuing development of an atherosclerotic plaque gradually restricts the blood flow in the affected artery and thereby leads to ischemia in the tissue supplied by the artery. Ultimately, the plaques become unstable and vulnerable to rupture with ensuing acute atherothrombotic events. Collectively, the various organ-dependent clinical manifestations are termed as atherosclerotic cardiovascular diseases (ASCVD) (Kavey et al., 2003). In the sub-endothelial space of an atherosclerosis-prone segment of an artery, the macrophage content at any time is determined by the

⁎ Corresponding author at: Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, P.O. Box: 91779-48564, Iran. E-mail addresses: [email protected], [email protected] (A. Sahebkar).

https://doi.org/10.1016/j.biocel.2020.105684 Received 17 June 2019; Received in revised form 2 December 2019; Accepted 2 January 2020 Available online 03 January 2020 1357-2725/ © 2020 Elsevier Ltd. All rights reserved.

International Journal of Biochemistry and Cell Biology 120 (2020) 105684

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Fig. 1. A schematic illustration of efferocytosis as a multi-step process and its-related molecules. Step one: “Find-Me” signals for requiring phagocytic cells and “Keep out” signal for neutrophils (Bournazou et al., 2009; Park and Kim, 2017). Step two (recognition step): Eat-Me” signal for ACs, which are recognized via phagocytic cells by phosphatidylserine (PtdSer) on surface of ACs and their bridge receptors or opsonization receptors on phagocytic cells such as milk fat globule-EGF factor 8 protein (MFG-E8) and a receptor tyrosine kinase of the TAM (MerTK), protein S and growth arrest-specific 6 (Gas6) and “Don’t Eat-Me” signal for living cells by CD47 and or CD31. Step three: Engulfment step such as cytoskeletal rearrangement regulation and digestion. Step 4: Processing, anti-inflammatory and tolerance signals as post-translational steps. In this step, phagocytic cells is indicated to trigger release of transforming growth factor-β (TGF)-β, interleukin -10, as well as prostaglandin E2 (PGE2), as anti-inflammatory cytokines and also tolerogenic signals to decrease immune reactions against self-antigens derived from AC (Hawkins and Devitt, 2013; Tajbakhsh et al., 2019b, 2018). Abbreviations: ApoE: Apolipoprotein E; BAI1: Brain angiogenesis inhibitor 1; C1q-CRT: C1q/Calreticulin; CD: Cluster of Differentiation; CX3CR: Chemokine (C-X3-C motif) Receptor; Fractalkine/ CX3CL1: Chemokine (C-X3-C motif) ligand 1; G2A: G-protein–coupled receptor; Gas6: Growth arrest-specific 6; ICAM3: Intercellular adhesion molecule 3; IL-10: Interleukin-10; LPC: Lysophosphatidylcholine; LRP: Low-density lipoprotein receptor (LDLR)-related protein 1; MFGE8: Milk fat globule epidermal growth factor-factor 8; P2Y2: Nucleotide receptors; PGE2: Prostaglandin E2; PtdSer: Phosphatidylserine; RAGE: Receptor for advanced glycation end products; S1P: Sphingosine-1 phosphate; S1PRs: Sphingosine-1 phosphate receptors; TAM: Family of receptor tyrosine kinases (including Tyro3, Axl, and MerTK); TGF-β: Transforming growth factor β; TIM1/3/4: T cell immunoglobulin and mucin domain1/3/4.

responses and plaque instability in advanced atherosclerotic plaques (Clarke et al., 2006; Seimon and Tabas, 2009). High levels of circulating low-density lipoprotein (LDL) are the leading cause of atherosclerosis (Ference et al., 2017). A high concentration of oxidized LDL (OxLDL) in atherosclerotic plaques induces aberrant apoptosis of the VSMCs and eventually potentiates plaque disruption and risk for ASCVD (Sun et al., 2017). In this regard, efferocytosis as an effective and timely phagocytosis of ACs by macrophages seems to relieve atherosclerosis to some extent in the early phase of atherosclerosis (Tajbakhsh et al., 2019a, b; Tajbakhsh et al., 2018). Importantly, as stated above, in early atherosclerotic lesions, in which the clearance of ACs is efficient, macrophage apoptosis seems actually to protect against atherosclerosis, since it leads to reduced cellularity of the lesions and to reduced lesion progression (Kockx et al., 1998; Kockx and Herman, 2000; Schrijvers et al., 2005). In contrast, enhanced apoptosis together with reduced AC clearance results in lesions with a necrotic core, i.e., in lesions susceptible to rupture and formation of a local platelet-rich arterial thrombus (Ait-Oufella et al., 2008; Schrijvers et al., 2007; Thorp et al., 2008, 2009) (Fig. 2). However, in advanced atherosclerotic plaques, an enhanced

balances between the relative rates of the influx of circulating monocytes and their conversion into macrophages, and macrophage survival and death (Back et al., 2019). This particularly applies to the most typical cells of atherosclerotic lesions, the foam cells. The foam cells are typically macrophages which have ingested plasma-derived apolipoprotein B-containing lipoproteins and have accumulated their cholesterol as cholesteryl-ester containing cytoplasmic lipid droplets. Importantly, in early atherosclerotic lesions, phagocytic clearance of apoptotic macrophages by efferocytotic mechanisms appears to be efficient, and, accordingly, macrophage apoptosis leads to diminished cellularity and to an attenuated progression of the lesions (Back et al., 2019; Tabas, 2005) (Fig. 2). Moreover, apoptotic death of macrophages and their rapid efferocytosis does not cause inflammation. In sharp contrast, in late atherosclerotic lesions, defective clearance of apoptotic macrophages leads to their secondary necrosis and to an ensuing proinflammatory response (Tabas, 2005, 2010) (Fig. 2). Thus, in late lesions, necrotic macrophages and macrophage foam cells gradually form a necrotic lipid core, which promotes further inflammation (Back et al., 2019). Moreover, apoptosis of vascular smooth muscle cells (VSMCs) and macrophages contribute to the development of pro-inflammatory 2

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Fig. 2. Caspase-dependent events in early and advanced atherosclerosis and their metabolic consequences. In early atherosclerosis, the exposed PtdSer is identified via efferocytosis molecules including milk fat globule-EGF factor 8 protein (MFG-E8), Protein S, and growth arrest-specific protein 6 (GAS6). Macrophages employ receptors for finding, catching, eating, and engulfing ACs. To inhibit inflammatory responses, the macrophages which have engulfed ACs subsequently generate and release two anti-inflammatory cytokines, IL-10 and transforming growth factor-β (TGFβ). (Nagata and Tanaka, 2017). In advanced lesions, the efficiency of efferocytosis is reduced, and, consequently, ACs accumulate and die due to secondary necrosis (Schrijvers et al., 2007; Seimon and Tabas, 2009). Mechanistically, activated inflammatory caspases activate caspase-3, which, again, leads to the process of DFNA5 as well as secondary necrosis (Rogers et al., 2017). Inflammatory caspase-mediated secondary necrosis leads to the release of damage-associated molecular patterns (DAMPs) including high-mobility group box 1 (HMGB1), DNA, RNA, ATP, and UPT. These DAMPs are recognized by receptor/pattern recognition receptors (PRRs) on the phagocytic cells, which lead to inflammatory responses (Kolb et al., 2017). Moreover, enhanced apoptosis together with reduced ACs clearance results in the formation of a necrotic lipid core, and renders the lesion susceptible to rupture and thrombosis formation (Ait-Oufella et al., 2008; Thorp et al., 2008, 2009).

caspase-dependent processes in atherosclerosis. Since the global burden of cardiovascular diseases (CVD) is still huge despite therapeutic advances in medication and new technologies, in this brief review we investigated the role of caspase-dependent events in efferocytosis and their possible effects on atherosclerosis, with an ultimate goal to contribute to the identification of candidate drug targets in this disease.

generation of apoptotic macrophages or formation of foam cells results in defective efferocytosis that triggers inflammatory responses and secondary necrosis of the ACs partially by the release of pro-inflammatory regulators (Tabas, 2005). As stated above, defective efferocytosis is intimately coupled with the progression of atheromatous plaques, and results in increased numbers of necrotic cells and subsequent formation of vulnerable plaques susceptible to rupture (Tabas, 2010; Tajbakhsh et al., 2018). Such vulnerable plaques, if eroded or ruptured, may lead to myocardial infarction, sudden cardiac death or stroke (Virmani et al., 2002). In this respect, the caspases involved in efferocytosis are acting in a timely manner in the ACs and macrophages of the evolving atherosclerotic lesions. Importantly, caspases (except caspase-14) are classified into two main groups, namely the group including caspase-1, -4, -5, -11 and -12, and the group including caspase-2, -3, -6, -7, -8, -9 & -10, the former ones being involved in inflammation signaling and the latter ones in apoptosis (Fernández Daniel and Lamkanfi, 2015). Caspases are involved in all steps of efferocytosis, i.e., in “Find-Me” signals, “Eat-Me” signals, engulfment, and anti-inflammatory responses. Thus, caspasedependent cellular events could be implicated in atherosclerosis through their efferocytosis-regulating effects (Pulanco et al., 2017; Yang et al., 2018). Based on the previous literature, only few studies have been conducted regarding the regulation of efferocytosis via

1.1. Efferocytosis signaling Efferocytosis, the phagocytic clearance of ACs, is a very complex biological system that involves many processes (Tajbakhsh et al., 2018) (Fig. 1). Generally, it involves several steps, including “Find-Me”/”Keep me out” signaling, “Eat-Me”/”Don’t Eat-Me” signaling, uptake/engulfment, processing, and finally, promotion of an anti-inflammatory response and tolerance (Park et al., 2007; Tajbakhsh et al., 2018). ACs release “Find-Me” signals, which trigger the migration of phagocytic cells towards the ACs (Tajbakhsh et al., 2018). ACs may also release “keep me” signal and prevent the migration of granulocytes, such as neutrophils and eosinophils, to the ACs (Bournazou et al., 2010, 2009). After “Find-Me” signaling, phagocytic cells identify the ACs by “EatMe” signals affected by ligands on the ACs (Tajbakhsh et al., 2018). It is suggested that phagocytic cells start engulfing, digesting and processing the ACs after "Eat-Me" activation. In the final step, the post-engulfment 3

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Fig. 3. Degradation of apoptotic DNA and exposure of phosphatidylserine (PtdSer) by caspase-dependent events. In non-apoptotic cells, caspase-dependent DNase (CAD) forms a heterodimer with ICAD in the cytoplasm of cells. After apoptotic stimuli, active caspase 3 or 7 cleaves ICAD at two positions to release CAD as a homodimer (Sakahira et al., 1998). DNA fragmentation is occurred apoptosis mediated by the homodimer of CAD in the nucleus. Moreover, caspase3/7 leads to exposure of “Eat-Me” signals such as PtdSer in the cell surface of ACs. In the plasma membrane of non-apoptotic cells, PtdSer is localized at inner leaflets of plasma membranes via the flippase action that is dependent ATP. When cells undergo apoptosis, caspases 3 and 7 cleave and activate the XK-related protein 8 (Xkr8) scramblase, whereas cleave and inactivates flippase (ATP11C), rapidly exposing PtdSer to the ACs surface (Nagata and Tanaka, 2017; Toda et al., 2015).

increase vascular adhesiveness and motility and clearance of ACs (Elliott and Ravichandran, 2016; Junger, 2011). It has been indicated that depletion of extracellular nucleotides or deletion of P2Y2 can lead to a delay in the clearance of ACs by macrophages (Elliott et al., 2009). The CX3CL1/fractalkine is another “Find-Me” signal that is released in the early stages of apoptosis (Truman et al., 2008). Recognition of the CX3CL1 released from ACs by the GPCR CX3C chemokine receptor 1 (CX3CR1) is critical for the recruitment of macrophages (Truman et al., 2008). Consequently, nucleotides and CX3CL1 are released early by apoptotic lymphocytes may have a role in the quick and efficient clearance of ACs in tissues (Elliott and Ravichandran, 2016). Other “Find-Me” signals, which include lysoPC and S1P accumulate later during the apoptotic process. LysoPC is released during apoptosis by caspase-mediated activation of the calcium (Ca2+)-independent phospholipase A2 (iPLA2). Importantly, lysoPC is a strong chemoattractant for monocytes and macrophages (Lauber et al., 2003; Ousman and David, 2000). S1P, another potent macrophage chemoattractant, accumulates extracellularly subsequent to the stimulation of apoptosis (Luo et al., 2016; Weigert et al., 2010). Moreover, it has been established that S1P release via ACs is associated with the activation of inflammatory caspases (Weigert et al., 2010).

step, the phagocytic cells start to generate anti-inflammatory cytokines and inhibitors, such as interleukin-10 (L-10), prostaglandin E2 (PGE2), and transforming growth factor beta (TGF-β) (Tajbakhsh et al., 2018). 1.1.1. “Find-Me” signals as the first step of efferocytosis and caspasedependent apoptotic cells in atherosclerosis “Find-Me” signals are one of the earliest and most important steps in efferocytosis. There are different kinds of soluble factors, which lead to an alarm from ACs to be sensed by phagocytic cells (Elliott and Ravichandran, 2016; Tajbakhsh et al., 2019b). Activation of executioner caspases throughout apoptosis results in the release of these soluble chemoattractants (Ravichandran and Lorenz, 2007). The effector caspase activation and morphological alterations in ACs are associated with an increase of the main “Find-Me” signals including: adenosine triphosphate ((ATP)/ uridine triphosphate (UTP), C-X3-C Motif Chemokine Ligand 1 (CX3CL1/fractalkine), lysophosphatidylcholine (lysoPC) as well as sphingosine-1-phosphate (S1P) (Elliott and Ravichandran, 2016). Activation of caspases 3 and 7 stimulates a cascade of enzymatic alterations, which leads to the morphological and biochemical features of apoptosis. The release of ATP and UTP from the cytoplasm of ACs closely associates with the activation of caspases (Chekeni et al., 2010; Qu et al., 2011). It has been indicated that the cleavage of the C-terminal tail of pannexin-1 monomers by the caspase3/7 results in the opening of the hexameric channels in the plasma membrane, which allows the extracellular release of cytosolic nucleotides (Chekeni et al., 2010). The extracellular nucleotides derived from ACs are identified by the phagocytic cells via the P2Y2 G-protein-coupled receptor (GPCR) (Elliott et al., 2009). P2Y2 has been revealed to

1.1.2. Apoptotic cell motility and caspase-dependent apoptotic cells Non-engulfed ACs are often seen in clusters at a specific site, a finding which well agrees with the notion according to which the movement of ACs increases the ability of phagocytes to locate them, thereby enhancing efferocytosis (Elliott et al., 2009; Elliott and Ravichandran, 2016). Apoptosis and cells undergoing apoptosis often 4

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to self-antigens (Ravichandran and Lorenz, 2007; Roszer et al., 2011; Tajbakhsh et al., 2018). Several factors and pathways are involved in the successful regulation of engulfment and digestion processes, and also in the related processes during the post-engulfment stage. Inflammatory responses and inflammation-associated caspase-dependent events in effective and defective efferocytosis

show quick and dynamic changes of the cytoskeleton that result in membrane blebbing and motility patterns characteristic of apoptosis (Elliott and Ravichandran, 2016). Rho-associated coiled-coil-containing protein kinase 1 (ROCK) activation by caspase causes dynamic alterations in the cytoskeleton and the plasma membrane resulting in nondirectional motility of ACs to enhance the probability of encountering a phagocyte (Coleman et al., 2001; Elliott and Ravichandran, 2016; Ohta et al., 2006). Caspase-3 cleavage of ROCK1 results in constitutive kinase activity, actomyosin contraction, myosin light chain phosphorylation and also blebbing (Atkin-Smith et al., 2015; Coleman et al., 2001; Sebbagh et al., 2001). It has been found that inhibition of ROCK-1 with Y-27632 leads to a decrease in early atheroma formation (Mallat et al., 2003).

1.1.5. The immunologically silent form of cell death mediated by caspasedependent apoptosis Whereas necrotic cells generally prompt inflammatory responses, ACs do not, and via releasing various anti-inflammatory molecules the ACs typically lead to anti-inflammatory responses in the effectively efferocytosing phagocytes of the immune system (Birge and Ucker, 2008; Cocco and Ucker, 2001; Martin et al., 2012). Importantly, even if apoptotic cells enter secondary necrosis and are leaking their cellular contents, they remain anti-inflammatory, which suggests that the proinflammatory activity of the of danger-associated molecules (DAMPs) present in the ACs or released by them is reduced (Szondy et al., 2017). DNA fragmentation is suggested to be a critical DAMP that results in dendritic cell maturation as well as immune responses (Marichal et al., 2011). The chromosomal DNA fragmentation into nucleosomal units is introduced as a critical hallmark of apoptosis (Steller, 1995; Wyllie, 1980). Indeed, one of the first lines of defense against nuclear factors, as DAMPs, is their degradation after release, followed by their clearance. DNA fragmentation with endonucleases reduces the ensuing immunological responses (Enari et al., 1998). For example, caspase-activated DNase (CAD) prompts the fragmentation of DNA in ACs (Figures 2 &3). Nucleosomes have been recognized on the cell surface of ACs, and they are present also in AC-derived microparticles (MPs) (Radic et al., 2004; Reich and Pisetsky, 2009). In ACs, genomic DNA undergoes hydrolysis to small fragments due to the actions of a CAD, also called the DNA fragmentation factor-40 (DFF-40) (Enari et al., 1998; Kawane et al., 2003; Liu et al., 1997; Sakahira et al., 1998). CAD is a magnesium‐dependent endonuclease, which is specific for double-stranded DNA and is responsible for the degradation of DNA during apoptosis (Enari et al., 1998). The CAD dimer has a scissor-like structure with an enzymatic active site (Woo et al., 2004) (Fig. 3). If either apoptotic or phagocytotic endonuclease activity is reduced, the incompletely digested DNA fragments ultimately lead to the development of autoimmunity (Enari et al., 1998; Kawane et al., 2003). Interestingly, knockout of CAD in ApoE−/− mice (i.e., generation of CAD−/− ApoE-/double-knockout mice) has been found to result in reduced macrophage apoptosis and inflammation in the atherosclerotic lesions (Chao et al., 2016). The lesions showed smaller necrotic cores and thicker fibrous caps, and thereby enhanced stability. Mechanistically, CAD deficiency protected against atherosclerosis by inhibiting macrophage apoptosis and inflammation at least partially due to inactivation of the mitogen‐activated protein kinase (MAPK) and kinase/extracellular signal‐regulated kinase 1 and 2 (MEK‐ERK1/2) signaling pathway in the ApoE−/− mice (Chao et al., 2016). Furthermore, it has been shown that the receptor for PtdSer on phagocytes is an important secretory signal for TGF-β release, and thereby for an anti-inflammatory response by the phagocyte (Huynh et al., 2002; Xiao et al., 2002). TGF-β is involved in plaque fibrosis and also in the resolution of inflammation in the atherosclerotic plaque (Nhan et al., 2005), and, as reflected by a reduction of expression levels of pro-inflammatory cytokines, such as IL‐6, IL‐1β, and tumor necrosis factor alpha (TNF‐α), and also by the prevention of nuclear factor kappa-light-chain-enhancer of activated B cells (NF‐κB) signaling (Brand et al., 1996). NF‐κB is involved in the regulation of atherosclerosis-related pro-inflammatory genes (Xanthoulea et al., 2005).

1.1.3. “Eat-Me” signals and caspase-dependent apoptotic cells The “Eat-Me” signal phosphatidylserine (PtdSer) is critically involved in the engulfment of ACs (Asano et al., 2004). Indeed, exposure of PtdSer on the cell surface links apoptosis with the clearance of ACs (Fadok et al., 1992; Luthi et al., 2009). Macrophages recognize the “EatMe” signals on the surface of dying cells. In non-ACs, PtdSer is limited to the inner side of the plasma membrane (Leventis and Grinstein, 2010), and such normal distribution of PtdSer in the plasma membrane is disrupted via scramblases in response to apoptotic stimuli. It is suggested that scramblases transport phospholipids independently of ATP between the inner and outer leaflets (Fig. 3). Transmembrane protein 16 F (TMEM16 F) and Xk-related protein 8 (Xkr8) are two forms of scramblases (Toda et al., 2015). TMEM16 F is a Ca2+- gated ion channel and Xkr8 localizes to the plasma membrane (Suzuki et al., 2013, 2010). Xkr8 must be cleaved via a caspase to stimulate phospholipid scrambling and exposure of PtdSer on the surface of cells. During apoptosis, Xkr8-deficient cells fail to reach cell surface exposure of PtdSer, and, accordingly, these cells are not engulfed by macrophages during apoptosis (Suzuki et al., 2013). In non-ACs, asymmetric phospholipid spreading between the inner and outer sides of the plasma membrane is maintained via an ATP-dependent aminophospholipid translocase or flippase, which is required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet (Tanaka et al., 2011). ATPase Phospholipid Transporting 11C (ATP11C) and cell cycle control protein 50A (CDC50A, also known as transmembrane protein 30A (TMEM30A)) form a hetero-complex (ATP11C/CDC50A) which has been identified to be responsible for the activity of flippase (Segawa et al., 2014). In this case, ATP11C has three sites for caspase-recognition, one for each of 3, 6, and 7 and cleavage via caspase throughout the apoptotic process inactivates its flippase activity. CDC50A is introduced that has a function as a chaperone for ATP11C. It is indicated that lack of CDC50A results in the exposure of PtdSer on the cell surface (Chao et al., 2011; Segawa et al., 2014). Collectively, Xkr8 activation and flippase inactivation lead to PtdSer exposure on ACs (Chao et al., 2011). It is well established that PtdSer exposure on cell surface is critical for efferocytosis (Fadok et al., 1992; Luthi et al., 2009). In this context, the TAM receptors Tyro3, Axl, and Mer can be activated via bridge molecules, such as protein S and growth arrest-specific 6 (Gas6) (van der Vorst et al., 2015). These bridge molecules enable the clearance of ACs by the reorganization of PtdSer and the receptor tyrosine kinase of the TAM (MerTK) on ACs and phagocytic cells, respectively (Chen et al., 1997; Hall et al., 2005). 1.1.4. “Engulfment signals” and caspase-dependent apoptotic cells After "Eat-Me" signaling, phagocytic cells continue to absorb, ingest and process the ACs, covering a process known as “engulfment signaling” in efferocytosis. During effective efferocytosis, the engulfment signaling results in digestion of the debris, inhibition of DAMPs release, increase of engulfment by other phagocytic cells, which in an atherosclerotic plaque, may result in inhibition of macrophage foam cell formation, anti-inflammatory responses, and maintenance of tolerance

1.1.6. Caspase-dependent events and high mobility group box-1 in defective efferocytosis The high mobility group box-1 (HMGB1) is another recognized DAMP, and it also acts as an alarmin. HMGB1 links to the DNA, and can 5

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pyroptosis-mediating caspases, has a role as a main player in stimulation of necrotic death (Wallach et al., 2016). In this regard, pyroptosis is activated via the stimulation of caspase-1 and caspase-11 in mice, and caspase-4/-5 in humans as inflammatory caspases (Miao et al., 2011). Although caspase-1/11 in double knockout macrophages cannot cleave and trigger GSDMD, they can trigger caspase-dependent necrosis after the mice have been infected with vesicular stomatitis virus (VSV) (Rogers et al., 2017). Furthermore, in addition to inflammatory caspase activity, there is another pathway in stimulation of necrotic death in inflammasome via the deafness, autosomal dominant 5 (DFNA5), that is mediated by microbial pathogens (Lamkanfi and Dixit, 2011; Rogers et al., 2017; Stewart and Cookson, 2016). The inflammasome is a multiple adaptor protein complex includes Nod-like receptors (NLRs) family members (Strowig et al., 2012). The NLRs are linked to an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) (Chen and Nunez, 2010). Within the cytosol of inflammatory cells, this domain recruits and activates caspase-1, which as an inflammatory caspase, activates the maturation of IL-1β and IL-18 and into forms capable of being secreted by the cells (Mariathasan et al., 2004). Interestingly, in experimental vascular injury in mice, ASC deficiency in bone marrow cells inhibited neointimal formation without affecting apoptosis in the vascular wall cells (Yajima et al., 2008).

be released as a DAMP by necrotic cells (Scaffidi et al., 2002). However, in ACs, caspases lead to inactivation of HMGB1 in two ways: directly, by remaining bound to chromatin due to the generalized hypoacetylation of histones, and indirectly by cleaving p75NDUF, a mitochondrial protein (Scaffidi et al., 2002). This event enhances the generation of reactive oxygen species (ROS), resulting in oxidation of HMGB1, and subsequently in neutralization of the pro-inflammatory activity of HMGB1 (Kazama et al., 2008). On the other hand, increased HMGB1 may lead to defective efferocytosis, and, thereby results in the development of an advanced atherosclerotic plaque. Indeed, an increase in the expression of HMGB1 leads to decreased efferocytosis in atherosclerotic plaques in vivo (Tao et al., 2015). Transfection of SR-BI−/− macrophages with SR-BI markedly decreased HMGB1, and knockout of HMGB1 partially restored efferocytosis in SR-BI−/− macrophages, suggesting that SR-BI regulation of HMGB1 impacts efferocytosis via other receptors (Tao et al., 2015). 1.1.7. Induction of immune tolerance via apoptotic cells requires caspasedependent oxidation of high mobility group box-1 Immune tolerance is vital for an effective immune system as well as for the self/nonself discrimination. Caspase activation triggers mitochondria to generate molecules belonging to the ROS, which are important to tolerance induction via ACs. ROS oxidizes the potential danger signal HMGB1 released from ACs, which neutralizes its stimulatory activity and enhances immune tolerance (Janko et al., 2014; Kazama et al., 2008). The production of ROS, as a result of caspase cleavage of p75, results in the immunological effects of ACs via the oxidation of HMGB1′s immunostimulatory activity (Kazama et al., 2008). It has been demonstrated that extracellular HMGB1, as a proinflammatory mediator, has an important role in the manifestations of CVD (Hu et al., 2009; Yan et al., 2009; Yao et al., 2013).

1.1.8.1. Caspase-dependent events result in activation of deafness, autosomal dominant 5- a possible mechanism for pyroptosis in atherosclerosis. Macrophage apoptosis decreases plaque growth in early atherosclerosis, but increases the necrotic core formation and also atherosclerotic plaque destabilization in advanced plaques (Arai et al., 2005; Gautier et al., 2009; Stoneman et al., 2007). Mechanistically, however, an enhanced rate of macrophage apoptosis leads to decreased AC clearance, and so stimulates plaque growth (Van Vré et al., 2012). In secondary necrosis, the complex of active caspase-9 (mitochondria receptor pathway) and caspase-8 (death receptor pathway) cleaves pro-caspase-3 to produce the heterodimer of active caspase-3 (Rogers et al., 2017). Subsequently, active caspase-3 cleaves the DFNA5, as another pathway of secondary necrosis, to produce the necrotic N-terminal DFNA5 fragments (DFNA5-N) that are capable of forming pores in the cell membrane (Rogers et al., 2017). Accordingly, when acting in the absence of inflammatory caspases, activation of caspase-3 as an apoptotic caspase can act to stimulate necrosis by cleavage of DFNA5 (Lamkanfi and Dixit, 2011; Rogers et al., 2017; Stewart and Cookson, 2016). In this line, in DFNA5−/− mice, the necrotic response of macrophages to the VSV infection is reduced (Rogers et al., 2017). The pores formed by DFNA5-N lead to the release of cellular contents of the dying cells, such as the DAMPs (pro-inflammatory mediators, HMGB1 and ATP) (Rogers et al., 2017). The DAMPs in macrophages can act as alarm signals to recruit immune cells to the site of apoptosis and secondary necrosis or pyroptosis (Rogers et al., 2017). It remains to be investigated whether caspase dependent activation of DFNA5 occurs in atherosclerotic lesions. Such DFNA5 activation could be of importance, as pyroptosis in smooth muscle cells and macrophages is a prominent feature of human atherosclerosis and is associated with atherosclerotic plaque instability (Xu et al., 2018).

1.1.8. The role of caspase-dependent events depending on the type of cell death Today, it has become clear that several distinct types of deathprompting mechanisms can result in different cell-death processes, such as apoptosis and necrosis (Wallach et al., 2016). As discussed above, apoptosis is generally stimulated through the activities of the individual members of the caspase family. This family can be involved in physiological and pathological conditions. In this line, during apoptosis the caspase family also has a role in efferocytosis by regulation of several events such as PtdSer exposure. A timely and quick efferocytosis leads to the engulfment of ACs, inhibition of DAMPs release, anti-inflammatory responses and maintenance of tolerance to the self-antigens (Fig. 1). In contrast, defective efferocytosis contributes to necrosis particularly in atherosclerotic lesions, where it critically contributes to the progression of the disease (Yurdagul et al., 2017). Caspase family has also a role in necrosis (Wallach et al., 2016). In this case, necrosis is suggested to be mediated via the necroptotic pathway (triggers of necroptosis) and the pyroptotic pathway (triggers of pyroptosis) (Wallach et al., 2016). The overexpression of these cell death-triggering proteins can stimulate necrosis and the rupture of the cell membrane, which lead to the release of cellular components, such as inflammatory cytokines and DAMPs (Wallach et al., 2016) (Fig. 2). Necroptosis is stimulated via activation of a specific protein known as the receptor-interacting protein kinase-3 (RIPK3) that phosphorylates the pseudokinase mixed lineage kinase domain–like protein (MLKL) (Linkermann and Green, 2014). Then, the phosphorylatedMLKL translocates to the plasma membrane and induces cell lysis (Wallach et al., 2016). The other type of cell death, pyroptosis, is initiated via caspases which are distinct from those mediating the apoptotic process. These caspases trigger the processing and secretion of inflammatory cytokines such as IL-1β as well as IL-18 (Wallach et al., 2016). Besides, gasdermin-D protein (GSDMD), when cleaved via the

1.1.9. Preclinical and clinical aspects of caspase-dependent events in atherosclerosis The relationships between factors/pathways as well as mediators that can be involved in the pathogenesis of atherosclerosis through caspase-dependent efferocytosis, as studied in vitro and in vivo in both rodent and humans, are listed in Table 1. For example, Tabas et al. showed that macrophage apoptosis is reduced in CAD−/−ApoE−/− mice on a high-fat diet (Tabas, 2010). Collectively, CAD deficiency has an anti-apoptotic effect, and thereby attenuates the development of atherosclerosis. Moreover, smaller necrotic cores were detected in 6

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Table 1 Caspase-dependent efferocytosis in atherosclerosis: Causative factors, pathways, mediators, and therapeutic opportunities. Modulators

Together with Caspase pathways

Atherosclerosis

Tested model(s)

↑Chronic Stress (Yu et al., 2018)

↑Caspase 3 & ↑Caspase 9

Rabbit Models of Chronic Stress

↑ALA-SDT (Yang et al., 2018)

↑Caspase-3 & ↑Caspase-9

↑ALA-SDT (Wang et al., 2018)

↑Mitochondria-caspase-3 pathway

↑Fas stimulation (Xue et al., 2017)

↑Caspase-3, & ↑Caspase-8, ↑FADD ↑Inhibition of caspase

↑ EEP, rich in flavones, (Tian et al., 2015)

↓Caspase-3

↑Isorhamnetin (Iso) (Luo et al., 2015)

↓Caspase-3

–

↓Caspase-1/11 (Hendrikx et al., 2015)

↑9-HODE & 13-HODE (Vangaveti et al., 2014) ↑ LA; α- (ALA) (Vangaveti et al., 2014)

↑Caspase-3/7

Chronic stress-induced reduced atherosclerotic medial area and increased plaque instability; ↑SMCs apoptosis and angiogenesis. ↓Fibrous caps; ↑Lipid cores. ↑Macrophages and new vessels; ↓SMCs and elastic fibers. ↓Atherosclerosis; ↑Efferocytosis; ↑Th2 polarization; ↑CD4+ cell apoptosis and macrophage-mediated phagocytosis; ↓Necrotic core size. ↓ Lipid content in plaque; ↑ Cholesterol efflux; ↑ Anti-inflammatory factor; ↑ PPARγ-LXRα-ABCA1/ABCG1 pathway; ↑ Foam cells apoptosis; &↑MerTK. High levels of FADD and caspase-8, but not caspase-3: ↑Incidence of coronary events. ↑Apoptotic level of VSMCs; ↑Stabilize plaque; ↓The risk of heart attack and stroke. ↓Vulnerable plaque progression via: ↓ER stress-mediated apoptosis; ↓Inflammatory response. ↓ACs numbers; ↓ Necrotic core area & ratio; ↓ Expression of NF-κB target gene. ↑Cleavage of DFNA5; ACs disassembly and progression to secondary necrosis; ↑Cleavage of DFNA5; ↑Secondary necrotic cells death. ↑Survival & ↓ cell death; ↑Phagocytosis and efferocytosis in macrophage foam cells; ↑Macrophage survival during ingestion of excess cholesterol; ↑Foam cell efferocytic function. ↑Apoptotic nuclei apparition, caspase-3 activation; ↑Cytochrome c release from mitochondria. Insertion genotype (II) of CASP8 −652 6 N del/ins and TT genotype of CASP3 rs4647601;G > T conferred risk for the development of coronary artery disease. ↑Caspase-3; ↓Endothelial healing subsequently carotid injury. ↓Cholesterol-induced caspase-3 cleavage by: ↓p38; ↑Bcl-2. ↓Caspase-9; ↓RIPK1 protein activity. ↑ Necrosis in Atherosclerotic Plaques; ↑ Plaque size and percentage necrosis; ↓ Macrophage content; Not changed collagen content and VSMC content. ↓Ox-LDL-induced lipid accumulation; ↓Caspase-3 activation and apoptosis induced by ox-LDL; ↓Ox-LDL- induced activation of ER stress signaling pathway. ↓Atherosclerosis by: ↓Macrophage apoptosis via: -PI3K/AKT activation as well as HO-1 induction; ↓ROS levels; ↓Lipid deposition; ↓Atherosclerotic plaque size. ↓Atherosclerosis development; ↑Anti-inflammatory blood leukocytes; ↓Level of Ly6Chigh monocytes; ↑Level of Ly6Clow monocytes. ↓Atherosclerotic plaque size; ↓Necrotic core content. ↑Caspase-3/7 activity.

No-effect Caspase-3/7

There was no effect of LA, or ALA agonist rosiglitazone.

↑AIF-targeting nanosensor (Sun et al., 2017) ↑Xuezhikang (Shen et al., 2017)

↓Apoptosis

–

↑Caspase-3 (Rogers et al., 2017)

↑Complement protein C1q (Pulanco et al., 2017)

↓Caspase-3

↑Ox-LDL acute treatment (Chen et al., 2017) ↑ Variants of Caspase genes (8 & 3) (Gundapaneni et al., 2017)

↑Apoptosis ↑Caspase-3 Caspase genes 8 & 3

↓miR-30c-5p (Ceolotto et al., 2017)

↑Caspase-3 expression

↑Atorvastatin (Bayatmakoo et al., 2017)

↓Cholesterol-induced caspase-3 cleavage

↑Simvastatin (Tuuminen et al., 2016)

↓Caspase-3, -8, & -9 mRNA expression ↓Caspase-3 (Grootaert et al., 2016)

–

ApoE−/−mice & in vitro

ApoE−/− mice and in vitro

In vitro & 4284 subjects In vitro

ApoE−/− mice & in vitro

DFNA5−/−mice & in vitro

In vitro

In vitro 300 CAD patients & 300 controls

C57Bl/6 J mice Wistar rats

Cardiac allograft ischemiareperfusion in Rat Casp3−/−ApoE−/− mice

In vitro

ApoE−/−mice

Casp-1/11−/−Ldlr−/− mice

In vitro

(continued on next page)

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Table 1 (continued) Modulators

Together with Caspase pathways

Atherosclerosis

Tested model(s)

↑CD137 (Jung et al., 2014)

↑Cleaved caspase-3

ApoE−/−CD137−/− mice

–

↑Caspase-3 & -7 (Luthi et al., 2009) ↑Caspase-1, -4, & -5 (Luthi et al., 2009) ↓CAD (Chao et al., 2016)

↑ VSMCs apoptosis via: ↓Antiapoptotic regulator, Bcl-2; ↑Cleaved caspase-3. ↓The stability of advanced atherosclerotic plaques. ↓IL-33 bioactivity.

– –

In vitro and in vivo

No effect on IL-33. ↓High‐fat diet‐induced atherosclerosis; ↓Atherosclerotic plaques; ↓Inflammatory response; ↓Macrophage apoptosis; ↑Stability of plaques; ↓In the phosphorylated levels of MEK‐ERK1/2.

atherosclerotic lesions in the CAD−/−ApoE−/− mice (Tabas, 2010). Of potential clinical significance has been the observation in atherosclerotic rabbits, in which caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions could be observed by radiolabeled annexin A5 imaging (Sarai et al., 2007). As extensive apoptosis of macrophages takes place at the site of plaque rupture in patients dying of acute coronary syndrome, caspase inhibition was considered as a potentially viable novel interventional strategy in acute coronary events. In inflammasome, caspase-1/11 activation stimulates IL-18, TNF-α, and IL-1β to be processed and released by local inflammatory cells in vascular inflammation and atherosclerosis (Eltzschig et al., 2012; Marques-da-Silva et al., 2011). Complete caspase-1 deficiency has been shown to protect against the growth of atherosclerosis (Chekeni and Ravichandran, 2011; Di Virgilio et al., 2001). Gage et al. indicated that the deficiency of caspase-1 reduced atherosclerotic plaque volume in the ascending aorta in vivo (Casp1−/−ApoE −/−) without influencing the levels of serum cholesterol or the distributions of lipoprotein-cholesterol in the hypercholesterolemic mice (Gage et al., 2012). There was also a reduction in the number of cells expressing the major histocompatibility complex (MHC) class II in the lesion in both sexes of mice, and also a reduction interferon (IFN)-γ in the lesions of female Casp1−/−ApoE -/- mice. (Gage et al., 2012). Moreover, Usui et al. demonstrated that atherosclerosis is reduced in the aortas and the aortic roots of Casp1−/ − ApoE−/− mice (Usui et al., 2012). In the double-knockout mice, the numbers of macrophages and VSMCs, and the expression levels of IL-1β in the plaques were reduced, and, in the blood the concentrations of IL1β, IL-1α, IL-6, CCL2, and TNF-α were reduced. Importantly, in this comprehensive study, it was observed that Ca2+ phosphate crystals in macrophages triggered the activation of caspase-1 and IL-1β and IL-1α secretion in vitro. Based on the results of this study, the authors suggested that caspase-1 as well as inflammasome may have an important role in the pathogenesis of atherosclerosis, and that the regulation of caspase-1 may be a potential target for inhibition of vascular inflammation and treatment atherosclerosis (Usui et al., 2012). However, the clinical drug development path to inhibit caspase-1 has been a challenge due to side effects (Kudelova et al., 2015). On the other hand, inhibitors of the NLRP3 inflammasome promise a considerable potential in inflammatory diseases (Mullard, 2019), and inhibition of the downstream endproduct, i.e., circulating IL-1β, has been successful in combatting the atherothrombotic events in patients with very advanced coronary atherosclerosis (Ridker et al., 2017). Thus, at the clinical level, it remains to be seen whether any molecular targets along the multiple pathways in caspase-dependent efferocytotic events in atherosclerosis will turn out to be successful targets in the future. Hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and has an important role in CVD

In CAD

−/−

ApoE−/− mice

progression. Interestingly, a rise in anti-inflammatory blood leukocytes, accompanied by a reduced level of Ly6Chigh monocytes and an enhanced level of Ly6Clow monocytes were reported in caspase-1/11−/ − Ldlr−/− mice, when compared with wild-type mice (Hendrikx et al., 2015). Hematopoietic deletion of caspase-1/11 led to a decrease in atherosclerotic plaque size, and, most importantly, necrotic core content was decreased in the caspase-1/11−/−Ldlr−/− mice. Grootaert and colleagues found that in Casp3−/−ApoE−/− mice bone marrow-derived macrophages (BMDM) and VSMCs are resistant to apoptosis, but prone to necrosis together with proinflammatory and prothrombotic properties (Grootaert et al., 2016). They found in such mice, that plaque and necrotic core sizes were increased, the macrophage contents were decreased, while those of VSMCs and collagen were not altered without changes in the concentrations of plasma total cholesterol, LDL cholesterol, or triglycerides, when compared with ApoE−/− mice. Collectively, the authors suggested that Casp3−/− prompts plaque growth and formation and growth of necrotic cores in ApoE−/− mice. Based on these results, an antiapoptotic approach via Casp3−/− is conductive and improves the stability of atherosclerotic plaques (Grootaert et al., 2016). Nevertheless, the identification of molecules intimately involved in necroptosis and pyroptosis may raise hope for treatment of atherosclerotic plaque (Wallach et al., 2016). As discussed above, Rogers et al. identified a molecular mechanism by which caspase-3-dependent cleavage of DFNA5 can result in secondary necrosis or pyroptosis (Rogers et al., 2017). Luo et al. indicated that isorhamnetin, an O-methylated flavonol extracted from a Chinese herb, inhibits oxLDL-induced macrophage injuries by reducing concentrations of ROS, lipid accumulation, and the activation of caspase-3, maintaining mitochondrial membrane potential, and controlling proteins associated with apoptosis. (Luo et al., 2015). Mechanistically, isorhamnetin's defensive impacts are caused by induction of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) binding and by heme oxygenase-1 (HO-1) induction. Importantly, in ApoE−/− mouse, isorhamnetin decreased atherosclerotic plaque volume and reduced macrophage apoptosis, and thereby inhibited atherosclerotic plaque development (Luo et al., 2015). 2. Conclusion Efficient engulfment of ACs by viable neighboring phagocytes is a critical endpoint of apoptosis that is required to inhibit secondary necrosis and also inflammation. In this context, caspases are pivotal in the multistep regulation of apoptosis and efferocytosis. Importantly, caspases are involved in atherogenesis in that they promote the recruitment of macrophages and the clearance of ACs, two closely linked processes, which together tend to inhibit the formation of a necrotic core and ensuing instability of an atherosclerotic plaque. Extant evidence suggests that, together with other pathways, caspase-dependent 8

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efferocytosis results in efficient removal of ACs, and also in inhibition of post-apoptotic necrosis. In future, functional studies are needed to aid our understanding of the significance of caspase alterations/ regulation as a target of therapeutic effects aimed at repairing insufficient or defective efferocytosis in the developing atherosclerotic lesions with a load of dying macrophage foam cells. Restoration of such caspase-dependent defective regulatory mechanisms may represent a therapeutic opportunity in this disease.

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Source of funding None. ABCA1: ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; BMDMs: Bone marrow-derived macrophages; ALA: α-linolenic acid; ALA-SDT: 5-aminolevulinic acid (ALA)- mediated sonodynamic therapy; CAD: Caspase-dependent DNase; EEP: Ethanol extract of propolis; FADD; Fas-associated death domain-containing protein; AIF: Apoptosis inducing factor; LA: Linoleic acid; LDH: Lactate dehydrogenase; MEK‐ERK1/2: Mitogen‐activated protein kinase (MAPK) kinase/extracellular signal‐regulated kinase 1 and 2; NFκB: Nuclear factor –kappaB; Ox-LDL: oxidized LDL; PPAR: Peroxisome proliferator-activated receptor; RIPK1: Receptor-interacting serine/ threonine-protein kinase 1; ROS: Reactive oxygen species; SMCs: Smooth muscle cells. Declaration of Competing Interest Dr. Banach has served on speaker’s bureau and as an advisory board member for Amgen, Sanofi-Aventis and Lilly. Other authors have no conflict of interests to disclose. Dr. Kovanen has served as a consultant to Amgen, Sanofi-Aventis, Raisio, and Unilever. Other authors have no competing interests to disclose. References Ait-Oufella, H., Pouresmail, V., Simon, T., Blanc-Brude, O., Kinugawa, K., Merval, R., Offenstadt, G., Leseche, G., Cohen, P.L., Tedgui, A., Mallat, Z., 2008. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28 (8), 1429–1431. Arai, S., Shelton, J.M., Chen, M., Bradley, M.N., Castrillo, A., Bookout, A.L., Mak, P.A., Edwards, P.A., Mangelsdorf, D.J., Tontonoz, P., Miyazaki, T., 2005. A role for the apoptosis inhibitory factor AIM/Spα/Api6 in atherosclerosis development. Cell Metab. 1 (3), 201–213. Asano, K., Miwa, M., Miwa, K., Hanayama, R., Nagase, H., Nagata, S., Tanaka, M., 2004. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J. Exp. Med. 200 (4), 459–467. Atkin-Smith, G.K., Tixeira, R., Paone, S., Mathivanan, S., Collins, C., Liem, M., Goodall, K.J., Ravichandran, K.S., Hulett, M.D., Poon, I.K., 2015. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat. Commun. 6, 7439. Back, M., Yurdagul Jr., A., Tabas, I., Oorni, K., Kovanen, P.T., 2019. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat. Rev. Cardiol. 16 (7), 389–406. Bayatmakoo, R., Rashtchizadeh, N., Yaghmaei, P., Farhoudi, M., Karimi, P., 2017. Atorvastatin inhibits cholesterol-induced caspase-3 cleavage through down-regulation of p38 and up-regulation of Bcl-2 in the rat carotid artery. Cardiovasc. J. Afr. 28 (5), 298–303. Birge, R.B., Ucker, D.S., 2008. Innate apoptotic immunity: the calming touch of death. Cell Death Differ. 15 (7), 1096–1102. Bournazou, I., Mackenzie, K.J., Duffin, R., Rossi, A.G., Gregory, C.D., 2010. Inhibition of eosinophil migration by lactoferrin. Immunol. Cell Biol. 88 (2), 220–223. Bournazou, I., Pound, J.D., Duffin, R., Bournazos, S., Melville, L.A., Brown, S.B., Rossi, A.G., Gregory, C.D., 2009. Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. J. Clin. Invest. 119 (1), 20–32. Brand, K., Page, S., Rogler, G., Bartsch, A., Brandl, R., Knuechel, R., Page, M., Kaltschmidt, C., Baeuerle, P.A., Neumeier, D., 1996. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J. Clin. Invest. 97 (7), 1715–1722. Ceolotto, G., Giannella, A., Albiero, M., Kuppusamy, M., Radu, C., Simioni, P., Garlaschelli, K., Baragetti, A., Catapano, A.L., Iori, E., Fadini, G.P., Avogaro, A., Vigili de Kreutzenberg, S., 2017. miR-30c-5p regulates macrophage-mediated inflammation and pro-atherosclerosis pathways. Cardiovasc. Res. 113 (13), 1627–1638. Chao, M.-L., Guo, J., Cheng, W.-L., Zhu, X.-Y., She, Z.-G., Huang, Z., Ji, Y., Li, H., 2016. Loss of caspase-activated DNase protects against atherosclerosis in apolipoprotein E-

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