TAPI-1 | Porcn Signal

Eﬀect of soluble cleavage products of important receptors/ligands on eﬀerocytosis: Their role in inﬂammatory, autoimmune and cardiovascular disease

Amir Tajbakhsha, Seyed Mohammad Gheibi Hayatb, Alexandra E. Butlerc,
Amirhossein Sahebkard,e,f,⁎
a Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
b Department of Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
c Diabetes Research Center, Qatar Biomedical Research Institute, Doha, Qatar
d Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
e Neurogenic Inﬂammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
f School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

A R T I C L E I N F O

Keywords: Ectodomain cleavage Shedding
A B S T R A C T

Eﬀerocytosis, the clearance of apoptotic cells (ACs), is a physiologic, multifaceted and dynamic process and a fundamental mechanism for the preservation of tissue homeostasis by avoiding unwanted inﬂammation and autoimmune responses through special phagocytic receptors. Defective eﬀerocytosis is associated with several

Abbreviations: ABCA7, ATP-binding cassette transporter A7; ACs, apoptotic cells; ADAM, A disintegrin and metalloproteinase; ALL, acute lymphoblastic leukemia; AMI, acute myocardial infarction; ApoE, apolipoprotein E; APP, acute phase protein; C1q, complement 1q; Ca2+, Calcium; Calr, calreticulin; CD, cluster diﬀer- entiation; CD14, cluster of diﬀerentiation 14; CD200R, CD200 receptor; CD32b, inhibitory FcγRIIb; CD47, cluster diﬀerentiation 47; Cdkn2b, cyclin dependent kinaseinhibitor 2B; CDKN2B, cyclin-dependent kinase inhibitor 2B; CLL, chronic lymphocytic leukemia; CRP, C-reactive protein; CTLA-4, cytotoxic T lymphocyte–asso-ciated antigen 4; CVD, cardiovascular disease; DAMPs, damage-associated molecular patterns; DAS/DAS28, Disease Activity Score; DCs, dendritic cells; DPC 333, ((2R)-2-((3R)-3-amino-3-2-oxopyrrolidinyl)-N-hydroxy-4- ethylpentanamide)); ECs, endothelial cells; eNOS, endothelial nitric oxide; ERK5, extracellular signalregulated kinase 5; esRAGE, endogenous secretory RAGE; FcγR/CD32b, Fc-Gamma Receptor; FcγR, Fc receptor; FL-RAGE, full length RAGE; G2A, G-protein–coupledreceptor; Gas6, growth arrest-speciﬁc gene 6 product; GPI, glycosyl phosphotidyl inositol; GWASs, genome-wide association studies; HDL, high-density lipoproteins; HETEs, hydroxyeicosatetraenoic acids; HMGB1, high mobility group box-1 protein; HODEs, hydroxy octadecadienoic acids; HUVECs, human umbilical vein en- dothelial cells; ICH, intracerebral hemorrhage; IFN-γ, interferon gamma; IgGR, the IgG receptors; IRF5, interferon regulatory factor 5; IRF8, interferon regulatoryfactor 8; ITIM, immunoreceptor tyrosine-based inhibitory motif; LDL, low density lipoprotein; LFA-1, lymphocyte function-associated antigen 1; LOX-1, lectin-likeoxidized low-density lipoprotein receptor-1; LPC, lysophosphotidylcholine; LPS, lipopolysaccharide; LRP, LDL receptor–related protein; ECs, endothelial cells; LRP1, low-density lipoprotein receptor (LDLR)-related protein 1; LysoPC, lysophosphatidylcholines; MAC, membrane attack complex; MAPK, mitogen activated kinase-likeprotein; mCD36, membrane CD36; M-CSF, macrophage colony-stimulating factor; MerTK, mer tyrosine kinase; MFG-E8, milk fat globule-EGF factor 8; MI, myo- cardial infarction; miRs, microRNAs; m-LOX-1, cell membrane; MMPs, matrix metalloproteinases; mPD-L1, membrane PD-L1; NCs, necrotic cells; NFκB, nuclear factor kappa-light-chain-enhancer of Activated B cells; Ox-LDL, oxidation of LDL; PAI-1, plasminogen activator inhibitor–1; PARP, poly(ADP-ribose) polymerase; PD- 1, programmed death-1; PECAM-1/CD31, platelet–endothelial cell adhesion molecule-1; PFC, per-ﬂuorocarbon emulsions; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol triphosphate; PKC, Protein Kinase C; PLC, Phospholipase C; PPAR-δ/γ, peroxisome proliferator-activated receptordelta/gamma; Pros1, protein S; PRRs, pattern-recognition receptors; Ps, phosphatidylserine; PTB, phosphotyrosine-binding; PTX3, pentraxin 3; RA, rheumatoid arthritis; RAGE, receptor for ad-vanced glycation endproducts; RANK, receptor activator of nuclear factor; RasGAP, activator protein of Ras-GTPase; ROS, reactive oxygen species; sCD163, soluble CD163; sCD200, soluble form of CD200; sCD200Fc, soluble CD200Fc; sCD36, soluble CD36; sCD47, soluble CD47; sCDllb/CD18, soluble CDllb/CD18; sFcγR/sCD32b, soluble forms of Fcγ receptors; SHIP, Src homology 2-containing inositol phosphatase; SHP, Src homology 2-containing tyrosine phosphatase; SIRP-α, signal reg- ulatory protein alpha; Sirt1, sirtuin1; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index score; sLOX-1, soluble form; sLRP, soluble form of LRP;

SM201, anti-FcγRIIB mAb; sMer, soluble form of MerTK; SOCS1, suppressor of cytokine 1; sPECAM-1, soluble PECAM-1; sRAGE, soluble Receptor for advanced glycation endproducts; SR-B1, scavenger receptor class B1; SSc, systemic sclerosis; STAT-1, signal transducer and activator of transcription 1; sTim, soluble Tim-3; suPAR/(CD87), soluble urokinase plasminogen activator receptor; TACE, tumor necrosis factor-alpha-converting enzyme; TCR, T cell receptor; TG2, transglutami-nase 2; Tim, T-cell immunoglobulin- and mucin-domain-containing molecule; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; TIMP-3, tissue in- hibitors of metalloproteinases; TLR, toll-like receptor; TLR3, toll-like receptor 3; TLR9, toll-like receptor 9; TLT2, TREM-like protein 2; TNF-RI, TNF receptor I; TNF- α, tumor necrosis factor-α; TRAF6, tumor necrosis factor receptor-associated factor 6; TRPC3, transient receptor potential canonical 3; TSP-1, thrombospondin-1; UCP2, uncoupling protein 2; UPA, urokinase plasminogen activator; Vit-K, vitamin K; VSMCs, vascular smooth muscle cells

⁎ Corresponding author at: Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran.
E-mail address: [email protected] (A. Sahebkar).

https://doi.org/10.1016/j.arr.2019.01.007

Received 26 October 2018; Received in revised form 4 January 2019; Accepted 8 January 2019
Availableonline09January2019
1568-1637/©2019ElsevierB.V.Allrightsreserved.

Target therapy Atherosclerosis Metalloproteinase Pharmacological eﬀects
disease states, including cardiovascular disease and impaired immune surveillance, as occurs in cancer and autoimmune disease. A major cause of defective eﬀerocytosis is non-functionality of surface receptors on either the phagocytic cells or the ACs, such as TAM family tyrosine kinase, which turns to a soluble form by cleavage/ shedding or alternative splicing. Recently, soluble forms have featured prominently as potential biomarkers, indicative of prognosis and enabling targeted therapy using several commonly employed drugs and inhibitors, such as bleomycin, dexamethasone, statins and some matrix metalloproteinase inhibitors such as TAPI-1 and BB3103. Importantly, to design drug carriers with enhanced circulatory durability, the adaptation of soluble forms of physiological receptors/ligands has been purported. Research has shown that soluble forms are more eﬀective than antibody forms in enabling targeted treatment of certain conditions, such as autoimmune diseases. In this review, we sought to summarize the current knowledge of these soluble products, how they are generated, their interactions, roles, and their potential use as biomarkers in prognosis and treatment related to in- ﬂammatory, cardiovascular, and autoimmune diseases.

1. Introduction

A growing body of literature has investigated clearance mechanisms of dying cells (apoptosis/necrotic bodies) in relation to critical disease, aiming to elucidate how body systems maintain homeostasis. Whilst immediate removal of dying cells with generation of healthy replace- ment cells is ideal, sometimes this process goes awry and either directly results in disease or indirectly contributes to disease initiation. In this regard, apoptotic cell (AC) phagocytosis by both professional and non- professional phagocytes, also known as eﬀerocytosis, is central to maintaining tissue homeostasis, immunological tolerance, and reg- ulating immune responses. Eﬀective eﬀerocytosis inhibits generation of necrotic cells (NCs) and thus maintains self-tolerance (Tajbakhsh et al., 2018). The immune response is a critical step in eﬀerocytosis and plays an important role in regulation of eﬀective eﬀerocytosis.

Based on research by Aggarwal et al., eﬀerocytosis is regulated
through pro-inﬂammatory and anti-inﬂammatory mediators (Aggarwal and Natarajan, 1996; Michlewska et al., 2009). Eﬀerocytosis is a re- markably adept mechanism, maintaining immune tolerance whilst permitting anti-bacterial immune responses (Hoﬀmann et al., 2001; van den Eijnde et al., 1998). Eﬀerocytosis is a multifaceted and dynamic process coordinated via the interaction of several surface molecules, chemotactic molecules, adaptor microRNAs (miRs) and opsonin mole- cules, each of which serves a vital role (Ocaña-Guzman et al., 2018; Tajbakhsh et al., 2018) (Table 1). The factors involved in eﬀerocytosis are either attached to the cell surface or present as soluble molecules in the microenvironment of the phagocytic cells. In this respect, epithelial and mucosal barriers, immune cells, pattern-recognition receptors (PRRs), soluble products, opsonins and cytokines are vital components of the innate defense system (Duﬃeld, 2003). Additionally, the diﬀer- entiation between ACs and live cells is determined by phagocytic re-
ceptors through recognition of “Don’t Eat- or Eat-Me” signals on the cell
surface (Abdolmaleki et al., 2018; Gheibi Hayat et al., 2018; Tajbakhshet al., 2018). Viable cells present the native “Don’t Eat-Me” signals, such as cluster diﬀerentiation (CD) 31, CD46, CD47, plasminogen ac- tivator inhibitor–1 (PAI-1) and C1q (Abou-Raya and Abou-Raya, 2006; Litvack and Palaniyar, 2010; Ocaña-Guzman et al., 2018), on their surface.

By contrast, ACs are no longer able to avoid complement up- take by macrophages and undergo removal through phagocytosis (Hakulinen et al., 2004). In addition, during the apoptotic process, cell surface blebs are produced comprised of intracellular components, some of which act as a “Find-Me” signal and alarm to phagocytic cells;
lysophosphatidylcholines (LysoPC) and nucleotides (e.g. naked DNA))
are examples. These blebs are released, their signaling initiating rapid and eﬀective cell clearance (Abou-Raya and Abou-Raya, 2006; Litvack and Palaniyar, 2010).

In some instances, the receptors and their ligands on phagocytic cells and ACs are intact, but eﬀerocytosis is defective. This is because soluble products are also involved in eﬀerocytosis; these come from phagocytosis receptors and involve shedding of ligand/receptor, re- sulting either in defective eﬀerocytosis or, conversely, more eﬃcient eﬀerocytosis (Driscoll et al., 2013; Enocsson et al., 2015; Gandhi et al., 2014). Generally, soluble receptors may be generated via 2 diﬀerent mechanisms: proteolytic cleavage of the full-length membrane-bound receptor or alternative splicing, one example being soluble receptor for advanced glycation end products (sRAGE) which can be generated by both pathways (Murase et al., 2000). Immune response regulation is one of the most important steps in eﬀerocytosis and phagocytic cells play an essential role in stimulation of either pro-inﬂammatory or anti- inﬂammatory responses (Duﬃeld, 2003; Rosenblum et al., 2015). So- luble factors/products regulate both the inﬂammatory and anti-in- ﬂammatory responses of phagocytic cells, as has been reported in sev- eral disease states, such as chronic inﬂammation, autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), atherosclerosis and cancer (Abou-Raya and Abou-Raya, 2006; Nativel et al., 2013; Tajbakhsh et al., 2018). Autoimmune disease

Table 1
The main molecules and pathways involved in eﬀerocytosis in inﬂammation and atherosclerosis.
Steps Molecules
Find Me signal Catch
Eat-Me signal ApoE4, Fas ligand (CD95 L), Fractalkine (CX3CL1), G2A, Lyso PC, LPC.
C1q, MFG-E8, TG2, Calr, LRP1, MerTK, Protein S, PTX3, SR-B1, Stabilin-2, Tim-1/Tim-4, TSP-1.
Don’t Eat-Me signal CD47, CD31, PAI-1, CD46, TIM-3, CD200, CD32b, PD-1 (CD-279).
Engulﬁng, process & anti-inﬂammatory TLT2, ABCA7, Cathepsin G, CDKN2B, ERK5, IRF8, p21Cip1 (CDKN1A), p38, p38 MAPK activity, PPAR-γ, PPAR-δ/γ, Sirt1, TLR3, TLR9, TRAF6, TRPC3, UCP2, IRF5.
Abbreviations in order of appearance: ApoE: Apolipoprotein E; G2A: G-protein–coupled receptor; LysoPC, Lysophosphatidylcholine; HMGB1: High mobility group box-1 protein; C1q: Complement 1q; MFG-E8: Milk fat globule-EGF factor 8; LPC: Lysophosphotidylcholine; TG2: Transglutaminase 2; LRP1: Low-density lipoprotein receptor (LDLR)-related protein 1; Calr: Calreticulin; MerTK: Mer tyrosine kinase; PTX3: Pentraxin 3; SR-B1: Scavenger receptor class B1; Tim: T-cell im-
munoglobulin- and mucin-domain-containing molecule; TSP-1:Thrombospondin-1; CD47: Cluster diﬀerentiation 47; PAI-1: Plasminogen activator inhibitor-1; TLT2: TREM-like protein 2; ABCA7: ATP-binding cassette transporter A7; MAPK: mitogen activated kinase-like protein; CDKN2B: Cyclin-dependent kinase inhibitor 2B; ERK5: Extracellular signal regulated kinase 5; IRF8: Interferon regulatory factor 8; PPAR-δ/γ: Peroxisome proliferator-activated receptor delta/gamma; Sirt1: Sirtuin1; TLR3: Toll-like receptor 3; TLR9: Toll-like receptor 9; TRAF6: Tumor necrosis factor receptor-associated factor 6; TRPC3:
Transient receptor potential
canonical 3; UCP2: Uncoupling protein 2; IRF5: Interferon regulatory factor 5; TIM-3: T-cell immunoglobulin and mucin-domain containing-3: CD32b: Inhibitory FcγRIIb.results from an imbalance between eﬀectors and controlling mechan- isms (Navegantes et al., 2017) and, therefore, it is critical to maintain immune cell tolerance. Atherosclerosis is associated with inﬂammation and the immune system plays a role in atherosclerotic plaque initiation/ progression in the intima (Tajbakhsh et al., 2018); whilst numerous studies have shown the importance of receptors and ligands in the development of atherosclerosis, few have studied the importance of soluble compounds/products and shedding of targets related to eﬀer- ocytosis. Hence, a greater understanding of the relationship between soluble products and their inhibitory/enhancing eﬀects on the phago- cytosis of ACs is crucial to allow for the design of appropriate treatment strategies (Litvack and Palaniyar, 2010). With this in mind, here we summarize the current state of knowledge regarding soluble products of receptor/ligand cleavage in inﬂammatory, autoimmune, and athero- sclerotic disease.

1.1. Molecules and pathways involved in eﬀerocytosis in atherosclerosis

Atherosclerosis is an inﬂammatory disease, and various factors and cells which are involved in inﬂammation might be implicated in the atherosclerotic plaque formation (Serhan et al., 2007). In addition, the development of atherosclerotic lesions is known to occur at vessel sites exposed to rapid changes in ﬂow and this leads to disturbed blood ﬂow (Chatzizisis et al., 2007). In this case, endothelial cells and related molecules, such as platelet endothelial cell adhesion molecule (PECAM- 1/CD31), have a vital role in sensing shear stress. The dysfunction of this sensing by endothelial cells is involved in the pathogenesis of atherosclerosis (Chatzizisis et al., 2007; Stevens et al., 2008).
Furthermore, macrophage apoptosis is complex and is involved in the atherosclerotic process (Tabas, 2005). In this regard, apoptosis and clearance of ACs, eﬀerocytosis, causes resolution of inﬂammation (Serhan et al., 2007). Eﬀective phagocytosis by macrophages and ef- ferocytosis appears to relieve atherosclerosis to some extent in the early phase of the atherosclerotic lesions (Tabas, 2005). Eﬀerocytosis inhibits formation of plaque vulnerability, and secondary necrotic cores, as well as acute luminal thrombosis (Ravichandran and Lorenz, 2007; Virmani
et al., 2002).

However, the increase in apoptotic macrophages or foam cell for- mation leads to defective eﬀerocytosis that stimulates inﬂammatory responses and also secondary necrosis of the ACs via the release of in- ﬂammatory regulators in advanced lesions (Tabas, 2005). This process occurs together with enhancement of the atheromatous plaques, leading to an increase of NCs and subsequent plaque rupture (Tabas and Bornfeldt, 2016). Both genetic and experimental studies have demon- strated that defective eﬀerocytosis is caused through dysregulation of receptors/ligands on the macrophages/ACs in atherogenesis (Kojima et al., 2017). Defective eﬀerocytosis in advanced atheroma is a primary cause of necrotic core formation and thus leads to further friable plaque formation, an important aspect in atherosclerosis (Tabas, 2010). The major molecules and pathways involved in eﬀerocytosis in inﬂamma- tion and atherosclerosis are indicated in Table 1.

1.2. The relationship of molecules/pathways and solubilization related to eﬀerocytosis

Numerous studies have revealed a number of membrane-anchored proteins that act as receptors or ligands and are released from the cell surface via cleavage by enzymes. The release of membrane proteins by cleavage has been purported to modify various cellular processes and is involved in a variety of disease pathologies (De Freitas et al., 2012; Driscoll et al., 2013; Friggeri et al., 2011; Gomez et al., 2012; Miller et al., 2010; Soto Pantoja et al., 2013; Vaisar et al., 2009). Recently, renewed interest in this process has stemmed from the fact that eﬀer- ocytosis is regulated via certain receptors and is important in resolution of inﬂammation. When soluble levels of certain AC receptors are ele- vated, dysfunctional clearance of ACs results (Boersma et al., 2005; Driscoll et al., 2013; Hsu et al., 2003; Kenis et al., 2006; Sather et al., 2007). In addition, proteolytic cleavage is a mechanism by which so- luble AC receptors can be released in chronic inﬂammation (Driscoll et al., 2013). Soluble receptors include the extracellular portions of receptors bound to membrane (Fig. 1) and can be produced from im- munoglobulins, adhesion molecule receptors, and even tyrosine kinase

Fig. 1. Schematic presentations of the soluble products of ligands on the apoptotic cells and their receptors may relate to “Don’t-Eat-Me” signal in the eﬀerocytosis. Cleavage of ligands on the apoptotic body, which act as “Don’t-Eat-Me” such as CD47, CD200 and PD-L1 may lead to increase of eﬀerocytosis.
PD-1: Programmed death-1; SIRPα: Signal regulatory protein alpha; Tim-3: T-cell immunoglobulin and mucin-domain containing-3; LRP-1: LDL receptor–related
protein; FcRIIb(CD32b): Fc-Gamma Receptor.receptors (Heaney and Golde, 1998). Hence, soluble receptors have been suggested as a source of accessible and non-invasive biomarkers (Tien et al., 2017). Furthermore, it is known that eﬀerocytosis and anti- inﬂammatory consequences are limited via proteolytic cleavage of AC receptors from the macrophage surface (Driscoll et al., 2013). Receptors related to eﬀerocytotic cleavage may result in reduction of eﬀerocytosis (Table 2). Thus, dysfunction of these enzymes or dysfunction of their regulators may result in defective eﬀerocytosis via increase of soluble receptors/ligands.

1.3. Inﬂammation resolution mediated by eﬀerocytosis

Resolution of inﬂammation, as part of the host response, is a co- ordinated and active process mediated through biosynthesis of active mediators and which leads to the restoration of tissue homeostasis (1, 2). Defective resolution can result in chronic inﬂammation, additional tissue damage, and dysregulation of tissue homeostasis. Moreover, de- fective resolution has been implicated in several diseases, including atherosclerosis and the progression of autoimmunity (Nathan and Ding, 2010; Serhan et al., 2007). Undoubtedly, defective eﬀerocytosis is an important hallmark of inappropriate inﬂammation resolution (Tabas, 2017). Eﬀerocytosis contributes to resolution of inﬂammation through several important steps, including recognizing and engulﬁng ACs, which prevents AC distribution and accumulation of the M1 phenotype together with secretion of inﬂammatory agents and also by release of
anti-inﬂammatory cytokines, such as IL-10, and TGF-β, which they re-
lease after eﬀective clearance of ACs via eﬀerocytosis (Tabas, 2017; Tajbakhsh et al., 2018). IL-10 and TGF-β have been implicated in NFκB suppression, and lead to inhibition of inﬂammation and restoration of tissue homeostasis (Cui et al., 2007; Fadok et al., 1992). IL-10 de- monstrated anti-atherogenic eﬀects through decreasing the inﬁltration
of monocytes to the atherosclerotic plaque (Caligluri et al., 2003; Liu et al., 2006).

1.4. Eﬀerocytosis regulation through ectodomain shedding by certain enzymes

Metalloproteases mediate cellular responses to stress by interacting with proteins at the cell surface. These enzymes regulate several pro- cesses such as ectodomain shedding, extracellular matrix binding, and proliferation (Fischer et al., 2004; Singh et al., 2009). Ectodomain shedding is an essential mechanism for membrane-anchored molecule proteolytic cleavage at the cell surface which results in the release of a soluble molecule into the microenvironment (Arribas and Borroto, 2002). Ectodomain shedding has a critical role in the modulation of immune responses through modulating the release of chemokines, cy- tokines, receptors of cytokines, and numerous membrane-anchored immuno-regulatory molecules (Chalaris et al., 2010; Garton et al., 2006). The metalloproteases are the main cleavage enzymes in cells, and play a central role in ectodomain shedding (Moss and Lambert, 2002). Tumor necrosis factor-alpha-converting enzyme (TACE/ ADAM17) is one of the most well-known of the ADAM family members. TACE inhibitors prevent the release of the soluble form of tumor ne-
crosis factor-α (TNF-α) (Moss and Lambert, 2002). ADAM17 sheds its
substrates at a membrane-proximal site (Caescu et al., 2009); it cleaves numerous proteins at the cell surface that are involved in inﬂammation (Garton et al., 2006; Murphy et al., 2008). Deletion of ADAM17 in- creases macrophage mediated eﬀerocytosis in vivo, leading to an aug- mented anti-inﬂammatory response (Driscoll et al., 2013). This shed- ding can prevent receptor function in macrophage-mediated AC engulfment (Sather et al., 2007). The soluble cleavage products may function as sequester ligands and decoy receptors (Sather et al., 2007). Shed receptors may act to regulate the biological activity of these li- gands via acting as agonists or antagonists (Daub et al., 2010; Ho et al., 2015; Peschon et al., 1998).

1.5. CD47 as a “Don’t Eat-Me” signal in eﬀerocytosis
In contrast to “Eat-Me” signals exposed on ACs, live cells expose
“Don’t Eat-Me” or “Not Ready to Eat” signals to prevent eﬀerocytosis,
which suppresses or controls the immune system (Fig. 1). In this re- spect, surface expression of some receptors, such as CD47 and CD31, inhibits activated phagocytes from attempting to engulf live cells (Gardai et al., 2006; Grimsley and Ravichandran, 2003). Live cells seems to have the ability to internalize CD47 on the cell surface; tumor cells also express CD47 on their surface to prevent eﬀerocytosis by phagocytic cells (Nilsson and Oldenborg, 2009). Soluble CD47 (sCD47), produced through proteolytic cleavage via MMP-2, has been target for therapy in recent years (Hsu et al., 2003; Miller et al., 2010; Soto Pantoja et al., 2013).

1.6. Eﬀerocytosis regulation through Calr/LRP1

LDL receptor-related protein 1 (LRP1) is a vital intermediary for eﬀerocytosis, as necessary ligands for stimulation of engulfment re- ceptors on phagocytic cells. LRP1 ligands have a key role in the in- hibition of atherosclerosis in eﬀerocytosis (Boucher et al., 2003; Lillis et al., 2008). LRP1 loss leads to inﬂammation of the vasculature, defects in eﬀerocytosis, increased necrotic core size, and extension of the atherosclerotic lesion. Remarkably, loss of these receptors in both professional eﬀerocytes, such as macrophages and dendritic cells (DCs), or in non-professional phagocytes, such as vascular smooth muscle cells (VSMCs), is suﬃcient to increase the speed of development of ather- ogenesis (Tajbakhsh et al., 2018). Apolipoprotein E (ApoE), as a LRP1 ligand, inhibits microglia activation via a mechanism involving LRP1 (Pocivavsek et al., 2009). LRP1 gene loss results in worsening of ex- perimental autoimmune encephalomyelitis in microglia in vivo (Chuang et al., 2016). LRP1 is cleaved and shed from cell surfaces through ADAM10, MMP-14, and ADAM17 and a soluble form of LRP (sLRP) is produced (Gorovoy et al., 2010; Pocivavsek et al., 2009; Yamamoto et al., 2017) (Fig. 1). The sLRP1 concentration is raised in the plasma of humans with RA and systemic lupus erythematosis (SLE), and in mice treated with lipopolysaccharide (LPS) (30). LRP1 stimulates in- ﬂammatory mediator expression via macrophages (30). Moreover, sLRP1 can bind active proteins, such as thrombospondin type 1 motif, member 5 (ADAMTS-5), MMP-13, and tissue inhibitors of

Table 2
The main enzymes that are related to the shedding of receptors/ligands, which are involved in eﬀerocytosis.

Molecules/regents Products

ADAM10, ADAM9, ADAM17, & Furin (11, 32, 39, 40) sMer, sAXL,
ADAM17 (41) sCD36
ADAM10 (42) sRAGE
ADAM10, ADAM17, & MMP-14 (43) sLRP
MMP-2 (30, 31) sCD47
MMP-3, MMP-8, MMP-9, & ADAM-10 (44) sCD46
Calpain (45) sPECAM-1
ADAM10, ADAM17 (32) Integrin beta 2
MMPs, elastase, plasmin, cathepsin G & Phospholipases (12) suPAR TACE, & ADAM17 (13) sKIM-1
MMP-9 &MMP-12(46) sCD14
ADAM17 (47) sFcγRIIIb
TACE, &ADAM17 (48) sTNF-RI
ADAM10, &ADAM17 (49) sTLR2
ADAM10, & ADAM17 (50) sCD163
MMP2 (51) sCD40
TACE, & ADAM17 (52, 53) sLOX-1
ADAM28 (54) sCD200
MMPs (55, 56) sCD93

ADAM: Metalloproteinase family; UPA: Urokinase plasminogen activator; MMPs: Matrix metalloproteinases; TNF-α: Tumor necrosis factor α; TACE: TNF- α converting enzyme; RAGE: Receptor for advanced glycation endproducts; LRP: LDL receptor–related protein; MQs: Macrophages; ECs: Endothelial cells.

metalloproteinases (TIMP)-3, thereby inhibiting endocytosis (a form of active transport, which moves particles, such as parts of cells, large molecules, or whole cells, into a cell such as a phagocytic cell) (Scilabra et al., 2013; Yamamoto et al., 2017). LRP1 on the surface of phagocytic cells is activated by calreticulin (Calr), on the surface of ACs which, in turn, prompts the engulfment process (Boucher et al., 2003; Gold et al., 2010; Lillis et al., 2008; Reddy et al., 2002). Moreover, the loss of the cyclin dependent kinase inhibitor 2B (Cdkn2b) gene of 9p21 locus re- sults in a reduction in Calr expression in atherosclerosis, causing re- sistance of phagocytic cells to eﬀerocytosis (Kojima et al., 2014; Nanda et al., 2016; Tajbakhsh et al., 2016). Genome-wide association studies
(GWASs) have discovered that the Calr ″Eat-Me″ ligand is decreased in
patients with cardiovascular disease (CAD) (Kojima et al., 2014, 2017).

1.7. Eﬀerocytosis regulation through platelet–endothelial cell adhesion molecule-1 (PECAM-1)/CD31
Previous studies have suggested that PECAM-1 (CD31) has a critical role in early and late stages of atherosclerotic plaque expansion in ApoE-/- mice (Caligiuri et al., 2005). PECAM-1/CD31 is expressed on endothelial cells (ECs), circulating leucocytes, and platelets and is in- tegral to cell extravasation from the vascular space through the en- dothelium. PECAM-1 plays a vital role in leukocyte trans-endothelial migration. Blocking EC functional PECAM-1 using anti-PECAM anti- body or soluble recombinant PECAM eﬀectively inhibits trans-en- dothelial migration of leukocytes into atherosclerotic plaques (Muller et al., 1993). PECAM-1 up-regulation due to high shear stress could lead to advanced atherosclerosis, as increased leukocyte inﬂux into the le- sion will cause aggregation of circulating platelets (Litwin et al., 1997). Raised levels of the soluble PECAM-1 (sPECAM-1) have been noted in a number of diﬀerent diseases, such as ischemic stroke (IS), athero- sclerotic disease, multiple sclerosis (MS) and acute myocardial infarc- tion (AMI) (Blann and McCollum, 1994; Losy et al., 1999; Serebruany et al., 1999; Zaremba and Losy, 2002). Wei et al. showed an association between PECAM-1/CD31 gene variations and sPECAM-1 levels in pa- tients with IS (Wei et al., 2009). Naganuma et al. proposed that calpain, an intracellular calcium (Ca2+)-activated cysteine protease, is activated by high shear stress at the intracellular domain, resulting in shedding/ cleavage of PECAM-1 (Naganuma et al., 2004). Losy et al. reported that sPECAM-1 is increased in sera of MS patients with active, gadolinium- enhancing lesions; sPECAM-1 has been suggested to play a role in the immune-modulatory mechanisms that prevent the migration of leuko- cytes in MS (Losy et al., 1999). Serebruany et al. reported that enhanced plasma sPECAM-1 may function as a biomarker for detection of patients with AMI (Serebruany et al., 1999).

1.8. Eﬀerocytosis regulation through CD46

CD46 is a type 1 glycoprotein, a cofactor which acts to protect au- tologous cells from complement-mediated damage (Liszewski et al., 2000). CD46 cross-linking leads to a reduction of IL-12 secretion on the cell surface of monocytes (Karp et al., 1996). Several studies have shown that CD46 can regulate production of IL-2 and IL-10 and also immune responses via eﬀects on CD8+ (cytotoxic) T cells and pro- liferation of CD4+ T cells (Elward et al., 2005; Marie et al., 2002). Elward et al. have shown that CD46 has a major role in innate immune
recognition of ACs and NCs as a “Don’t Eat-Me” signal (Elward et al., 2005). During AC formation, CD46 translocates into the membrane
from membrane stores and cytoplasmic/nuclear compartments. CD46 reduction leads to enhanced C3b deposition on the surface of ACs that attracts macrophages (Elward et al., 2005) (Fig. 2). CD46 cleavage via metalloproteinase is repressed by TAPI-1 and BB3103, two MMPs/ TACE inhibitors often used experimentally (Hakulinen et al., 2004). Soluble CD46 (sCD46) cleavage from NCs form micro-particles of ACs that are enriched for CD46 (Elward et al., 2005). NC supernatants were extremely sCD46-enriched. NCs lack CD46 signal without involving the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase 3. In contrast to what was previously thought, robust PARP and caspase 3 signals accompanied the lack of CD46 in the cytoplasmic or membrane and nuclear fractions in the ACs models (Elward et al., 2005). Cells induced to apoptosis quickly lost CD46 both in vitro and in vivo (Elward et al., 2005). An association has been shown between a reduction of CD46 and caspase 3 expression in vitro and the membrane attack complex (MAC), which was identiﬁed on NCs possibly as a consequence of CD46 cleaving into sCD46 (Elward et al., 2005). The MAC pores cause ion ﬂux and inﬂuence several critical signaling pathways, with a number of downstream events. Much of the activity stimulated by MAC pore is highly pro-inﬂammatory (Morgan, 2016). The activation of complement and C1q binding and C3b is regularly accompanied via protein activation of the terminal complement complex and accumu- lation of the MAC, which in turn may result in cell lysis (Muller- Eberhard, 1986).

1.9. Eﬀerocytosis regulation through soluble CD200

The CD200 receptor (CD200R) is an anti-inﬂammatory glycoprotein expressed on the surface of myeloid cells, mainly in the M2a phenoty- pical proﬁle of macrophages, as an anti-inﬂammatory response protein (Wright et al., 2000). CD200 suppresses macrophage-mediated phago- cytosis in vitro (Ocaña-Guzman et al., 2018). Interestingly, interaction of CD200R and its ligand, CD200, prevents macrophage activation and enhances phagocytosis (Ocaña-Guzman et al., 2018). Thus, on balance,
ImageFig. 2. The role of CD46 and sCD46 in eﬀer- ocytosis. During AC formation, CD46 has been shown translocating into the membrane from membrane stores and cytoplasmic/nuclear compartments. CD46, a cofactor protein, binds to C3b and C4b to promote their cleavage
mediated by factor I and leads to a “Don’t-Eat- Me” signal following an increase of iC3b (Liszewski et al., 2000). In contrast, CD46 re-
duction by cleavage by matrix metalloprotei- nases (MMP-8, MMP-9) and Disintegrin and metalloproteinases (ADAM-10), lead to en- hanced C3b deposition on the surface of ACs that attracts MACROPHAGEs (Elward et al.,

2005). MMPs:
Matrix
metalloproteinases;

ADAMs: Disintegrin and metalloproteinases.

inhibition of macrophage activation can modulate immune disease but can promote tumor growth. The CD200R interaction with CD200 (as a ligand) in macrophages prompts phosphorylation of tyrosine residues present in the intracellular portion of CD200R, a family of non-receptor tyrosine kinases. The phosphorylation of residues of CD200R causes the adaptor protein Dok2 to bind to the phosphorylated tyrosine (PTB) which, in turn, initiates an inhibitory signaling cascade (Mihrshahi et al., 2009). When Dok2 is bound to the intracellular portion of CD200R, other proteins, like the activator protein of Ras-GTPase (RasGAP), may become involved (Mihrshahi et al., 2009). Prior re- search has suggested that recruitment of RasGAP is critical for pre- venting the signaling pathways of Ras-ERK and PI3K in human mac- rophages (Mihrshahi et al., 2009). Ras-ERK and PI3K pathways are vital for proliferation, cell growth, diﬀerentiation, and metabolism via acti- vation of other transcription factors such as signal transducer and ac- tivator of transcription 1 (STAT-1). Moreover, STAT-1 is involved in
macrophage activation via interferon gamma (IFN-γ) (Josephs and
Sarker, 2015).

Twito et al. showed that CD200 cleavage by ADAM28 on B cells produces a soluble form of CD200 (sCD200) in serum (Twito et al., 2013) (Fig. 1). Expression of ADAM28 mRNA is associated with plasma sCD200 levels in chronic lymphocytic leukemia (CLL). siRNA for ADAM28 reduced sCD200 release from CD200+ cells that were already transfected with ADAM28 gene into CD200+ cells, thus having in- creased sCD200 release (Twito et al., 2013). Wong et al. proposed sCD200 as a non-invasive prognostic marker and therapeutic target for CLL (Wong et al., 2012).
Of interest are the diﬀerences between sCD200 and sCD200R1. sCD200 rescued macrophage fusion to form osteoclasts and macro- phage activation downstream of receptor activator of nuclear factor (RANK), a member of the tumor necrosis factor receptor superfamily; by contrast, sCD200R1 prevented this process (Gorczynski, 2012). Furthermore, sCD200 acts through Treg activation. Treg activation led to
T-cell inhibition via Treg cell surface cytotoxic T lymphocyte–associated
antigen 4 (CTLA-4) and ligands of programmed death-1 (PD-1) (PD-L1/ 2). The interface between sCD200, tumor CD200, and Treg CD200R leads to Treg activation and T-cell inhibition (Ring et al., 2017).

Li et al. demonstrated that CD200 was increased in early apoptotic cells when compared to live cells in SLE patients. Moreover, they sug- gested that expression and function of CD200 and CD200R1 are ab- normal in SLE (Li et al., 2012). The interaction of CD200R1 via CD200 was found to require signaling through stimulating docking protein 2 phosphorylation or the adaptor protein DOK2 (p56doc-2). Soluble CD200Fc (sCD200Fc) may stimulate CD200/CD200R1 signaling via an eﬀect on phosphorylation of DOK2 in CD4+ T cells. It is known that CD200Fc prompts DOK2 phosphorylation in CD4+ T cells. Thus, sCD200Fc via CD200R is an agonist of the CD200/CD200R1 signaling pathway, while the anti-CD200R1 antibody is an antagonist and has the potential to block the interaction between receptor and its ligand (Li et al., 2012).

1.10. The interaction of eﬀerocytosis molecules and PD1-PDL-1

PD-L1, an immune checkpoint molecule, is expressed on macro- phages, dendritic cells (DCs), T and B cells (Freeman et al., 2000). PD- L1 causes an inhibitory signal, which leads to the induction and maintenance of peripheral tolerance. PD-L1 is involved in the selection of T cells (positive and negative) in thymus (Keir et al., 2006). The expression of PD-L1 is promoted by MerTK as an immune checkpoint ligand to antagonize CD8+ T cells on the tumor cells (Nguyen et al., 2014). In this way, tumour cells may use MerTK-driven eﬀerocytosis for cancer progression (Nguyen et al., 2014). Moreover, PS by regulation of TAM receptors leads to PD-L1 expression on cancer cells, which may result in tumor immune progression and chemoresistance (Kasikara et al., 2017). PD-L1 has soluble forms and sPD-L1 levels are elevated when MMPs cleave the extracellular fraction of membrane PD-L1(mPD-L1) (Chen et al., 2011) (Fig. 1). Consequently, the production of sPD-L1 is repressed via MMP inhibitors (Chen et al., 2011; Dai et al., 2014). Remarkably, sPD-1 and sPD-Ll have been shown to have oppo- site regulatory eﬀects (Li et al., 2016). sPD-1 displays both functional agonism and antagonism. sPD-1 as an antagonist blocks and prevents the downstream immune regulatory eﬀects of membrane bound PD-1on T cell activation. sPD-1 as an agonist shows immune regulation via limiting T cell receptor (TCR) prompted events (Kuipers et al., 2006; Song et al., 2011). In contrast, sPD-L1 binds to the PD-1 receptor on the T cell that then releases an inhibitory signal, thereby preventing acti- vation and proliferation of T cells (Li et al., 2016).

Furthermore, Hassan et al. suggested that sPD-1 may have a role in
the pathogenesis of RA since RA patients have raised levels of sPD-1, which are associated with Disease Activity Score (DAS/DAS28), and could therefore be a useful marker reﬂecting RA disease activity (Hassan et al., 2015).

1.11. Eﬀerocytosis regulation through TIM

T-cell immunoglobulin- and mucin-domain-containing molecule (TIM)-3, as a negative regulator of T cell-mediated immune response, contributes to the phagocytosis of ACs through phosphatidylserine (Ps) and subsequently has a function in eﬀerocytosis. (Kobayashi et al., 2007; Nakayama et al., 2009). Receptors, such as members of the TIM family, are utilized by phagocytic cells to internalize the AC detritus. In
this respect, TIM-1 and 4 have been identiﬁed as bonding to PS (as an important “Eat-Me” signal in the eﬀerocytosis) (Kobayashi et al., 2007) and TIM-3 may also bond to phospholipids such as PS (Nakayama et al., 2009). Tim-3 has potential to exert an eﬀect on eﬀerocytosis through regulation of macrophages and T cells, as blocking Tim-3 signaling by
injection of soluble Tim-3 (sTim) signiﬁcantly increased CD36 expres- sion in peritoneal macrophages and reduced inﬂammation in the liver. Tim-3 signaling may prevent macrophage activity and phagocytosis in vivo (Wang et al., 2017). A study by Geng et al. concluded that Tim-3 has a critical role in Th1-mediated auto- and alloimmune responses. This early evidence suggested that sTim-3 has a inhibitory eﬀect on T cell-mediated immune response (Geng et al., 2006).

1.12. Eﬀerocytosis regulation through TAM family (e.g., sMrt, sAXL)

The TAM family includes TYRO3, AXL, and MerTK receptor tyrosine kinases, which have complex and diverse roles in cell biology. The best known ligands for TAMs are the vitamin K (Vit-K) modiﬁed γ-car-
boxylated proteins, growth arrest-speciﬁc gene 6 product (Gas6) and
protein S (Pros1), which are important ligands in eﬀerocytosis (Anderson et al., 2003; Mark et al., 1996). AXL/MertK promote eﬀer- ocytosis and trigger anti-inﬂammatory responses in macrophages through prevention of Toll-like receptor (TLR) signaling and enhance- ment of suppressor of cytokine 1 (SOCS1) and SOCS3 expression. SOCS proteins are intracellular, and inhibit cytokine signaling in various cell types (Rothlin et al., 2007; Zagorska et al., 2014). MerTK and AXLfunction are essential to immune homeostasis and accelerate im- munoregulatory functions in atherosclerosis, Parkinson’s disease, in- tracerebral hemorrhage (ICH) and inﬂammatory and autoimmune dis- eases such as systemic lupus erythematosis (SLE) and MS (Chang et al., 2018; Nguyen et al., 2014; Recarte-Pelz et al., 2013).

In addition,MerTK regulates pyrenocyte engulfment via central macrophages in erythroblastic islands and stimulates acute lymphoblastic leukemia (ALL) survival in the central nervous system (Krause et al., 2015; Toda et al., 2014). MerTK is expressed via macrophages and thus stimulates clearance of ACs and prevents the inﬂammatory response (Choi et al., 2013). The expression of MerTK is heterogenous among macrophage
subsets, being frequently limited to anti-inﬂammatory “M2c” cells,
diﬀerentiated through macrophage colony-stimulating factor (M-CSF) or glucocorticoids (Ambarus et al., 2012). Moreover, there is a soluble form of MerTK (sMer) in serum. The extracellular domain shedding ofMerTK receptor via macrophages acts as a decoy, resulting in athero- sclerosis and phagocytosis (Law et al., 2015). Shedding of MerTK and AXL via ADAM9, ADAM10, ADAM17, and Furin (leads to increased mature ADAM10) contributes to soluble receptor forms (Chang et al., 2018; Suresh Babu et al., 2016; Weinger et al., 2009) (Fig. 3). MerTK and AXL may be cleaved from the cell membrane, reducing accessibility of cell surface receptors for initiation under inﬂammatory conditions (Caescu et al., 2009). The MerTK is cleaved via ADAM17, resulting in production of sMer (Thorp et al., 2011b). SMer and sAXL can be identiﬁed in the blood and tissue and sMer interferes with the binding of MerTK to ProS and GAS6. Disorders of AXL/MerTK ligand binding or deﬁciency of AXL/MerTK prevents AC eﬀerocytosis and increases in- ﬂammatory cytokine production (Seitz et al., 2007). The sMer presents the inactive protein and prevents macrophage AC eﬀerocytosis in mice (Sather et al., 2007).

Cleavage of the MerTK receptor is facilitated via ADAM17 protein via a pathway requiring reactive oxygen species (ROS), p38 mitogen activated protein kinase (MAPK), and protein Ki- nase C (PKC), in vivo (Thorp et al., 2011a).
Conditions that result in an increase of ADAMs in cells leads to an
increase of sMer. SMer is increased in response to high glucose treat- ment in macrophages, and it is associated with the increased expression of ADAM9 in human diabetic failing heart tissues (Suresh Babu et al., 2016). Additionally, several compounds resulting from the oxidation of hydroxy octadecadienoic acids (HODEs)) and polyunsaturated fatty acids (hydroxyeicosatetraenoic acids (HETEs) and are contained in the necrotic core of carotid plaques stimulate ADAM17 and may result in shedding of the MerTK extracellular domain and a rise to sMer in human carotid plaques (Schrijvers et al., 2007; Tabas, 2005). Defective eﬀerocytosis causes development of the necrotic core, one factor con- tributing to plaque rapture and acute luminal thrombosis (Garbin et al., 2013).

MicroRNAs (miRs) modulate biological processes in disorders such
as atherosclerosis, inﬂammation and wound healing. Mir-126 has a wide range of targets including cytokines and transmembrane proteins (Suresh Babu et al., 2016). Babu et al. reported that diabetes con- tributes to a reduction in miR-126 expression which, in turn, leads to ADAM9 up-regulation (Suresh Babu et al., 2016). Over-expression of ADAM9 results in formation of inactive sMer by proteolytic cleavage of MerTK (Suresh Babu et al., 2016).
1.13. Eﬀerocytosis regulation through sTNF-RI

TNF-α and its receptors (TNF receptor I (TNF-RI) and TNF-RII) are present in soluble form, generated by extracellular domain cleavage of membrane integrated receptors (Galvani et al., 2000). Recent reports
have suggested that more extensive damage to surrounding tissues, necrosis and an increase in chronic inﬂammation could be due to in- creased production of TNF-α at sites of inﬂammation which, in turn,
result in repression of eﬀerocytosis by neutrophils. Dexamethasone
mimics the function of the anti-inﬂammatory cytokine IL-10 by pre- venting the generation of TNF-α in monocyte-derived macrophages (Michlewska et al., 2009). Furthermore, dexamethasone augments
phagocytosis in monocyte-derived macrophages exposed to TNF-α. LPS and TNF-α prevent eﬀerocytosis of neutrophils via monocyte-derived macrophages. The soluble form of TNF-RI (sTNF-RI) allows eﬀective eﬀerocytosis by binding extracellular TNF-α and thereby reducing its biological activity (Michlewska et al., 2009).

In addition, TNF-α is cleaved through TACE into a soluble cytokine. The active TNF-α release is decreased in ADAM17-deﬁcient mice (Mohan et al., 2002). MMP1 and MMP-9 also are able to cleave pro-TNF
(Mohan et al., 2002) (Fig. 4E). sTNF-RI is a chimeric protein containing a fragment crystallizable (Fc) region of human IgG1 (homodimer form) and has been shown to be a more potent inhibitor of TNF-α than the monomeric soluble form (Aggarwal and Natarajan, 1996). Galvani et al.
suggested that sTNF-RI has potential as a prognostic factor in cancers such as melanoma (Galvani et al., 2000). Additionally, Michlewska et al. found that sTNF-RI reduced LPS prevention of phagocytosis (Michlewska et al., 2009).

1.14. Eﬀerocytosis regulation through CD163+

Macrophage activation leads to various phenotypes based upon diﬀerent stimuli. Macrophages can be activated toward an M2 pheno- type by IL-4, IL-10, and IL-13 (Higashi-Kuwata et al., 2009). M2 mac- rophages are associated with important cellular processes, including eﬀerocytosis, neovascularization and wound healing (Mosser and Edwards, 2008; Zhong et al., 2018). Enhanced eﬀerocytotic capability has been shown for M2 phenotypes, which can release anti-in-
ﬂammatory cytokines, including TGF-β, as well as IL-10 (Huynh et al.,
2002; Zhong et al., 2018).

M2 macrophages (CD163+) have many receptors, including CD163, the hemoglobin scavenger receptor (Mosser and Edwards, 2008). Prior
ImageFig. 3. Shedding of MertK and AXL, as a TAM family, via the ADAM9, ADAM10, and ADAM17, contribute to receptor so- luble forms (Chang et al., 2018; Suresh Babu et al., 2016; Weinger et al., 2009). MertK and AXL may be cleaved from the cell membrane, reducing accessibility of the cell surface re- ceptors for initiation under inﬂammatory conditions (Caescu et al., 2009). MerTK is shown to be cleaved via ADAM17 re- sulting in production of sMer (Thorp et al., 2011b). SMer could complicate the binding of MerTK with ProS and GAS6 (Seitz et al., 2007). Moreover, reduction in miR-126 expres- sion, which in turn leads to ADAM9 up-regulation (Suresh Babu et al., 2016). Given that, over-expression of ADAM9 results in formation of inactive sMer by proteolytic cleavage of MerTK (Suresh Babu et al., 2016).
MMPs: Matrix metalloproteinases; ADAMs: Disintegrin and
metalloproteinases; miR: MicroRNA; MerTK: Mer tyrosine kinase;

Schematic showing the soluble products relating to the major receptors of eﬀerocytosis. Cleavage of these receptors may lead to reduction of eﬀerocytosis. A: suPAR is produced by MMPs, elastase, plasmin, cathepsin G & Phospholipases (Enocsson et al., 2015). B: sLOX-1 is produced by TACE & ADAM17 (Dreymueller et al., 2012; Zhao et al., 2011). C: sRAGE is produced by ADAM10 (Herold et al., 2007). D: sKIM-1 is produced by TACE, & ADAM17 (Gandhi et al., 2014), sCD14 is produced by MMP-9 and MMP-12 (Senft et al., 2005), sCD36 is produced by ADAM17 (Novak and Thorp, 2013). E: sCD163 is cleaved by ADAM10, & ADAM17 (Zhi et al., 2017) sTNF-RI is produced by TACE, &ADAM17 (Ichimura et al., 1998). F: αLβ2 integrin is produced by ADAM10, ADAM17 (Gomez et al., 2012).

MMPs: Matrix metalloproteinases; ADAMs: Disintegrin and metalloproteinases; ADAM: Metalloproteinase family; UPA: Urokinase plasminogen activator; MMPs:
Matrix metalloproteinases; TNF-α: Tumor necrosis factor α; TACE: TNF-α converting enzyme; RAGE: Receptor for advanced glycation end products; LRP: LDL receptor–related protein; MQs: Macrophages; ECs: Endothelial cellsresearch suggests that CD163 can be shed from monocytes and mac- rophages to induce soluble CD163 (sCD163) in response to pathological inﬂammatory conditions (ZHOU et al., 2016). SCD163 shedding is ef- fected by proteolytic enzymes (Hintz et al., 2002). CD163 cleavage is eﬀected by MMPs activated by oxidative stress, and an inﬂammatory
stimulus results in release of sCD163 (Shimizu et al., 2012). LPS can enhance the levels of sCD163 mediated by ADAM17 (Periyalil et al., 2015) (Fig. 4E). After shedding into the circulation, sCD163 is stable and detectable in serum.

Oxidative stress (e.g. diabetes mellitus), in- ﬂammatory stimuli (e.g. hemorrhagic fever with renal syndrome), andwound healing (e.g. ﬁbrotic diseases and the remodeling of connective tissues) can result in release of sCD163 from the cell surface through proteolytic cleavage (Frings et al., 2002; Levy et al., 2007; Wang et al., 2014). The signiﬁcant negative association demonstrated between membrane CD163 expression and sCD163 levels suggests that plasma sCD163 may arise from circulating monocytes (Davis and Zarev, 2005). Furthermore, sCD163 actively prevents lymphocyte proliferation and T- lymphocyte activation (Timmermann et al., 2004). Greisen et al. re- ported that sCD163, a speciﬁc M2 macrophage activation marker, correlates with disease activity markers before treatment in early RA (Greisen et al., 2015). Levels of sMer, which are associated with sCD163 levels, correlate with SLE Disease Activity Index (SLEDAI) score (Zizzo et al., 2013a). MerTK and CD163 are both able to stimulate release of IL-10 from M2c phenotypes, as well as protecting macrophages against oxidative stress and consequent apoptosis (Anwar et al., 2009; Nielsen et al., 2010; Zizzo et al., 2012). Increased release of sMer and sCD163 may result in defective functioning of M2c macrophages, which could then lead to defective eﬀerocytosis, chronic inﬂammation, and auto- immunity (Zizzo et al., 2013b). Hassan et al. reported raised serum sCD163 serum levels in patients with systemic sclerosis (SSc), a chronic autoimmune disorder, suggesting that macrophages are involved in the pathogenesis of systemic sclerosis (Hassan et al., 2016).

1.15. Eﬀerocytosis regulation through Cluster of diﬀerentiation 14 (CD14)

Monocyte surface molecule CD14 is a central element in the im- mune response. CD14 is a glycosyl phosphotidyl inositol-(GPI)-an- chored membrane glycoprotein expressed on macrophages/ monocytes, and neutrophils (Haziot et al., 1988). Cell surface CD14 binds to LPS and non-microbial ligands in the presence of LPS binding protein, contributing to activation of TLRs and downstream pro-inﬂammatory pathway signaling (Tobias and Ulevitch, 1993; Wright et al., 1990). Recent research suggests that CD14 is involved in inﬂammation and apoptosis (Männel and Echtenacher, 2000). CD14 also presents as a soluble form (sCD14) (Bazil et al., 1989) (Fig. 4D). Surface expression of CD14 is reduced after cell activation in monocytes and sCD14 is released (Buﬂer et al., 1995). Two sources are responsible for genera- tion of sCD14, secretion from liver and through enzymatic cleavage of GPI-anchored cell membrane-bound CD14 (Bazil et al., 1989; Durieux et al., 1994; Pan et al., 2000). sCD14 may result in activation by LPS of cells with mCD14 which includes ECs and SMCs (Juan et al., 1995; Pugin et al., 1993). LPS is an activator of monocytes and prompts production of sCD14. Various TLR ligands can cause CD14 down-reg- ulation on monocytes (Shive et al., 2015). The sCD14 dimer could be inﬂuenced by AC clearance and involved in eﬀerocytosis (Litvack andPalaniyar, 2010). Defective AC clearance occurred in CD14–/– mice.

Thephosphatidylglycerol present on the dying cells, as a ligand, is re- cognized by CD14. (Kuronuma et al., 2009; Litvack and Palaniyar, 2010; Numata et al., 2010). Previous studies have shown that sCD14 levels enhance inﬂammatory diseases and atherosclerosis (Juan et al., 1995; Pugin et al., 1993; Reiner et al., 2013). A study by Reiner et al. demonstrated that sCD14 predicts incipient cardiovascular disease (CVD), especially in older age people (Reiner et al., 2013). IL-6 prompts hepatic expression of sCD14 in response to inﬂammation (Bas et al., 2004). Circulating sCD14 is regarded as an acute phase protein (APP), one of many proteins stimulated in the early response to inﬂammation (Bas et al., 2004).

1.16. Eﬀerocytosis regulation through endogenous secretory RAGE (esRAGE) as a soluble form

The receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor, and regulates responses to cell danger, damage, and stress (Ma et al., 2012). RAGE is expressed at low levels in adult cells such as macrophages (Demling et al., 2006). RAGE is now known to act as a PS receptor on alveolar macrophages, which
leads to recognition and AC clearance (Friggeri et al., 2011; He et al., 2011). RAGE mediates responses to both forms of inﬂammation, in- cluding acute and chronic, and is complicated in several disease such as diabetes, atherosclerosis, cancer development and Alzheimer’s disease (Hudson et al., 2008; Ma et al., 2012; Yan et al., 2009). RAGE also exists as a soluble (sRAGE) and is formed via both proteolytic cleavage of full length (ﬂ)-RAGE and alternative mRNA splicing, a soluble form called endogenous secretory (esRAGE) (Kalea et al., 2009; Zhang et al., 2008) (Fig. 4C). SRAGE is formed via proteolytic cleavage of the mRAGE through ADAM10 (Kalea et al., 2009; Zhang et al., 2008). SRAGE has two functions, including: decoy receptor and pro-inﬂammatory. SRAGE can act as an extracellular decoy receptor, antagonizing ﬂ-RAGE and other receptors through binding damage-associated molecular patterns (DAMPs), and preventing leukocyte recruitment in chronic and acute inﬂammatory response (Herold et al., 2007).

However, sRAGE de- monstrates pro-inﬂammatory properties via interface with Mac-1, as a pro-inﬂammatory phenotype (Liliensiek et al., 2004; Pullerits et al., 2006). SRAGE repressed inﬂammation in IL-10-/- mice, reduced acti- vation of nuclear factor kappa-light-chain-enhancer of activated B cells(NFκB), and decreased expression of inﬂammatory cytokines such as Il-12 (Chavakis et al., 2004; Hofmann et al., 1999). The reduced ability to engulf apoptotic neutrophils and thymocytes was demonstrated in the macrophages from transgenic RAGE-/- mice. RAGE can increase eﬀer- ocytosis by binding to PS on pretreated RAGE+/+ macrophages. RAGE overexpression leads to an enhanced ability to engulf ACs in human embryonic kidney 293 cells. Additionally, treatment with sRAGE in- creases phagocytosis of ACs via macrophages in both RAGE+/+ and RAGE-/- animals (Friggeri et al., 2011).

1.17. Eﬀerocytosis regulation through soluble integrin beta 2 (β2) (CD11b)

The integrin family of transmembrane receptors is involved in the interactions between cells and their environment which, in turn, reg- ulate several functions integral to cellular physiology, including cell proliferation, diﬀerentiation, and migration (Winograd-Katz et al., 2014). In this respect, the main members of the integrin family, which
regulate leukocyte-endothelial interactions, are the β2 integrins lym- phocyte function-associated antigen 1 (LFA-1) (αlβ2; CD11a/CD18), the β1 integrin VLA-4 (α4β1; CD49d/CD29), and Mac-1 (αMβ2; CD11b/CD18) (Ley et al., 2007). A large number of these adhesion
proteins are cleaved and shed via ADAM10 and ADAM17 (Garton et al., 2006; Gjelstrup et al., 2010). Gomez et al. demonstrated shedding mediated by the metalloproteinase integrin β2 leads to stimulation of macrophage eﬄux from inﬂammatory zones, and the release of het-
erodimers of soluble integrin.

These events may limit local inﬂamma- tion (Gomez et al., 2012). Previous research showed proteolytic clea- vage of integrin β2 (soluble integrin β2) increases the resolution of inﬂammation by macrophages via active MMP-9 in vitro and in vivo (Vaisar et al., 2009) (Fig. 4F). Antagonism of phagocyte interactionswith iC3b and inﬂamed endothelium can be achieved with human so- luble CDllb/CD18 (sCDllb/CD18) and its functional form. Expression of a recombinant sCDllb/CD18 seems to preserve functional integrity. SCDllb/CD18 binds to iC3b in vitro (Dana et al., 1993). Previous re- search indicates that opsonization via iC3b results in a rise in AC en- gulfment by the CD18/CD11b and CD18/CD11c expressed on macro- phages (Mevorach et al., 1998). CD11b is vital for the engulfment of iC3b-opsonized ACs by macrophages (Mevorach et al., 1998). A study by Schif-Zuck et al. found that macrophages convert from the CD11bhigh to the CD11blow phenotype after interaction with ACs ex vivo. Subse- quently, macrophages with CD11blow engulfed apoptotic PMN more than macrophages with CD11bhigh; eﬀective eﬀerocytosis produces CD11blow macrophages, which are vital for resolving acute inﬂamma- tion (Schif-Zuck et al., 2011).

1.18. Eﬀerocytosis regulation through soluble urokinase plasminogen activator receptor suPAR/ (CD87)

uPAR is a multi-ligand receptor expressed on several cell types, such as macrophages and neutrophils. uPAR and its receptor are involved in a range of processes, such as inﬂammation, proteolysis, cell migration, and angiogenesis (Thuno et al., 2009). uPAR is a GPI-anchored protein (Yang et al., 2010). In addition to the receptor form of uPAR, there is a soluble form of this receptor (suPAR) (Fig. 4A). SuPAR has been sug- gested as an inﬂammation biomarker, and is involved in tissue in sev- eral diseases including cardiovascular disease (CVD), SLE, rheumatic diseases, hepatitis, renal disorders, and carcinoma (Berres et al., 2012;D’mello et al., 2009; Sehestedt et al., 2011; Sjöwall et al., 2015; Thuno
et al., 2009; Wei et al., 2011). Park et al. revealed enhanced macro- phage eﬀerocytosis of apoptotic neutrophils when uPAR was knocked- out in either neutrophils or macrophages.

Interestingly, when both macrophages and neutrophils were knocked-out, eﬀerocytosis did not increase (Park et al., 2009). Eﬀerocytosis improved when exogenous suPAR was added to cell lines or in vivo (Park et al., 2009). Yang et al. veriﬁed that uPAR recognizes and internalizes ACs in vivo and in vitro. AC engulﬁng activity was reduced by macrophages in uPAR−/− mice. SuPAR and polyclonal anti-uPAR antibodies repressed the internaliza- tion of ACs via macrophages which, in turn, reduce eﬀerocytosis. Based on a study by Yang et al., there was no defect in uPAR−/− macrophage uptake of live cells, but there was a defect for ACs. Phagocytosis mediated by uPAR of ACs was blocked via annexin V in the presence of Ca2+ in a HEK 293 cell line expressing human full-length uPAR (293- uPAR). Lack of kininogen, a uPAR-binding protein, in serum decreased the engulfment of ACs in vitro (Yang et al., 2010). Hodges et al. sug- gested that suPAR is a prognostic marker of atherosclerosis in CVD (Hodges et al., 2015).

1.19. Eﬀerocytosis regulation through sCD36

The CD36 receptor plays a major role in the uptake of modiﬁed LDL, leading to lipid loading in macrophages (Kunjathoor et al., 2002). CD36 proteolysis, mediated by ADAM17, is a critical post-translational me- chanism for the regulatory phagocytosis of ACs, in inﬂammation and inﬂammatory resolution (Driscoll et al., 2013). Macrophage CD36 surface levels are higher when ADAM17 is lacking, which results in a reduction in soluble CD36 (sCD36) levels (Driscoll et al., 2013) (Fig. 4D). ADAM17 cleaves membrane CD36 (mCD36) on macrophages which results in shedding of sCD36. Blocking of CD36 eliminates ef- ferocytosis via Adam17-null macrophages, a process that also leads to more rapid resolution of inﬂammation in vivo. Loss of CD36 results in decreased eﬀerocytosis which delays inﬂammation resolution. Expres- sion of CD36 stimulates eﬀerocytosis and an anti-inﬂammatory re- sponse in macrophages, increasing inﬂammation resolution in ADAM17−/− macrophages (Novak and Thorp, 2013). Chmielewski et al. indicated that sCD36 levels were associated with diabetes mel- litus, type 2 diabetes risk and chronic kidney disease (Chmielewski et al., 2010; Handberg et al., 2010). The levels of sCD36 have been suggested to predict cardiovascular mortality in patients (Chmielewski et al., 2010).

2. Beneﬁts of soluble products in eﬀerocytosis as targets

2.1. Soluble receptors as therapy

Soluble receptors have been suggested as a novel form of therapy in clinical medicine. Soluble receptors are attractive as anti-cytokine mediators. They have some advantages over anti-cytokine antibodies, including high speciﬁcity, high aﬃnity binding, and ability to stimulate the immune response. Moreover, the soluble receptors are easily dis- tributed within a ﬂuid compartment oﬀering an added advantage to their function in human disease. Soluble receptors could be engineered
to improve or change their biological activity. Beside being targeted therapies, they can also act as disease markers, allowing a simple blood draw to oﬀer information concerning diagnosis, prognosis and about eﬀective clearance of intravenously controlled colloidal drug carriers. Furthermore, soluble receptors may act like hormones. Below, we outline some advantages of soluble receptors.

2.2. Therapeutic inhibition of soluble TNF promotes remyelination by increasing myelin phagocytosis by microglia

Karamita et al. showed that sTNF production stimulates the pro- inﬂammatory function of microglia in demyelination in the brain. Moreover, sTNF prevents the eﬀective function of phagocytic CNS macrophages in clearing debris of myelin and permitting remyelination in a mouse model of demyelination and remyelination. Thus, selective inhibition of sTNF through CNS-penetrating molecules, XPro1595 and TNF-signaling inhibitor for example, oﬀers a potential therapy for sti- mulating remyelination and neuroprotection in diseases such as mul- tiple sclerosis (MS) (Karamita et al., 2017).

2.3. Using sCD47 as an inhibitor of the uptake of perﬂuorocarbon emulsions (PFC) by macrophages

Rapid clearance of colloidal drug carriers such as liposomes, poly- plexes, and emulsions via the mononuclear phagocyte system is a major problem for drug delivery (Moghimi et al., 2001). There have been numerous studies to investigate the ability of the circulatory durability of colloidal drug carriers as therapeutic materials. In this respect, PE- Gylation seems to be a popular approach for regulating particulate surfaces to prolong circulatory lifetimes (Collard et al., 2000). De- signing compatible colloidal carriers or other carriers with enhanced circulatory durability have a similar physiologic basis to soluble form of receptors/ligands (Moghimi et al., 2001). A study by Hsu et al. in- vestigated the potential of sCD47 to prevent uptake of per-ﬂuorocarbon emulsions (PFC) via macrophages (Hsu et al., 2003). They showed that it is possible to use sCD47 protein to antagonize phagocytosis of col- loidal drug carriers by macrophages (Hsu et al., 2003).
2.4. “Velcro” engineering of high aﬃnity CD47 ectodomain as signal regulatory protein α (SIRPA) antagonists that enhance antibody-dependent cellular phagocytosis

Velcro engineering is a potent tool to improve protein-protein in- teractions. Velcro-CD47 may be used as an adjuvant for im- munotherapy for cancer in vitro. Signal regulatory protein alpha (SIRP-
α) is blocked by soluble high aﬃnity CD47 (shaCD47). CD47, as a marker of self on cancer cells, activates SIRPα on macrophages, re- cruiting Src homology region 2 domain-containing phosphatase-1 (SHP-
1) and -2 tyrosine phosphatases and inhibiting phagocytosis of cancer cells by macrophages. ShaCD47, as a competitive antagonist, inhibits the CD47 on the surface of cancer cells from engaging SIRPα on mac-
rophages (Ho et al., 2015).

2.5. Recombinant soluble CD93 proteins with EGF-like domains (rCD93D123, with domains 1, 2, and 3; and rCD93D23, with domains 2 and 3)

Work on rCD93D23 has shown that it is more potent than rCD93D123 in promoting the proliferation and migration of human umbilical vein endothelial cells (HUVECs). MMP-2 generation was en- hanced after the HUVECs were treated with rCD93D23. Additionally, rCD93D23 stimulated diﬀerentiation of HUVECs via phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide (eNOS) synthase and ex- tracellular signal-regulated kinases-1/2 signaling. Studies show that the soluble EGF-like domain comprising CD93 protein is a angiogenic factor acting on the endothelium (Kao et al., 2012).

2.6. Inhibition of foam cell formation using a soluble CD68-Fc fusion protein

Lipid-rich atheromatous plaque weakening via dependent degrada- tion by MMP leads to an increased incidence of acute coronary events. Hence, prevention of MMP activity is of great importance in reduction of unstable angina and myocardial infarction (MI) (Rouis, 2005). CD68 belongs to class D of the scavenger receptors and is a member of the lysosomal-associated membrane protein family. CD68 is found in sev- eral cell types, including macrophages, Langerhans cells and dendritic cells (DCs), and it binds and internalizes modiﬁed lipoproteins (Ramprasad et al., 1996). Daub et al. provided evidence that CD68-Fc decreased macrophage foam cell formation in vitro. This was caused both by interference of CD68-Fc with OxLDL uptake into macrophages and platelets and by preventing phagocytosis of platelet/OxLDL. MMP expression in macrophages was repressed by CD68-Fc treatment. Fur- thermore, CD68-Fc decreased MMP-9 activity, a critically important protease in foam cell production, atheroprogression, and plaque rup- ture (Daub et al., 2010). Therefore, CD68-Fc appears to be a new tool for inhibition of macrophage foam cell formation (Daub et al., 2010).

3. Conclusion

With regard to eﬀerocytosis, recent work has highlighted alternative ways that ACs can be recognized. Eﬀerocytosis is closely linked to the immune system and is involved in many aspects of macrophage-medi- ated clearance such as modulation of MMPs and production of soluble receptors. The immune system can use a varied range of opsonins and receptors to sense the existence of late ACs/NCs, a process which could lead to the recruitment of additional phagocytes to sites of inﬂamma- tion and modulate the appropriate immune response. Speciﬁc decrease or blocking of inﬂammatory regulators or direct administration or sti- mulation of the mediators in anti/soluble forms that increase the sup- pressive action of macrophages may have therapeutic potential. Additionally, monitoring soluble receptor levels may provide additional information about human diseases, serving as biomarkers or prognostic markers. Special soluble receptors such as CD47 could serve as en- hancers of drug half-life in the circulation. Greater understanding of eﬀerocytosis and the role of soluble products should prompt further research to more fully delineate this pathway and, ultimately, to design more eﬀective treatments. Thus, eﬀerocytosis is an important topic, and warrants additional research.

Conﬂict of interest

There is no conﬂict of interest to declare.

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