Efferocytosis and Its Associated Cytokines: A Light on Non-tumor and Tumor Diseases?
2020; Elsevier BV; Volume: 17; Linguagem: Inglês
10.1016/j.omto.2020.04.010
ISSN2372-7705
AutoresDanfeng Lin, Xiaodiao Kang, Lu Shen, Sheng Tu, Cameron Lenahan, Yiding Chen, Xiaochen Wang, Anwen Shao,
Tópico(s)Blood properties and coagulation
ResumoBillions of cells undergo turnover and die via apoptosis throughout our lifetime. A prompt clearance of these apoptotic cells and debris by phagocytic cells, a process known as efferocytosis, is important in maintaining tissue homeostasis. Accordingly, impaired efferocytosis due to the defective clearance and disrupted stages can lead to a growing number of inflammation- and immune-related diseases. Although numerous studies have shown the mechanisms of efferocytosis, its role in disorders, such as non-tumor and tumor diseases, remains poorly understood. This review summarizes the processes and signal molecules in efferocytosis, and efferocytosis-related functions in non-tumor (e.g., atherosclerosis, lung diseases) and tumor diseases (e.g., breast cancer, prostate cancer), as well as describes the role of involved cytokines. Of note, there is a dual role of efferocytosis in the abovementioned disorders, and a paradoxical effect among non-tumor and tumor diseases in terms of inflammation resolution, immune response, and disease progression. Briefly, intact efferocytosis and cytokines promote tissue repair, while they contribute to tumor progression via the tumor microenvironment and macrophage politzerization. Additionally, this review provides potential targets associated with TAM (TYRO3, AXL, MERTK) receptors and cytokines, such as tumor necrosis factor α and CXCL5, suggesting potential novel therapeutic ways in treating diseases. Billions of cells undergo turnover and die via apoptosis throughout our lifetime. A prompt clearance of these apoptotic cells and debris by phagocytic cells, a process known as efferocytosis, is important in maintaining tissue homeostasis. Accordingly, impaired efferocytosis due to the defective clearance and disrupted stages can lead to a growing number of inflammation- and immune-related diseases. Although numerous studies have shown the mechanisms of efferocytosis, its role in disorders, such as non-tumor and tumor diseases, remains poorly understood. This review summarizes the processes and signal molecules in efferocytosis, and efferocytosis-related functions in non-tumor (e.g., atherosclerosis, lung diseases) and tumor diseases (e.g., breast cancer, prostate cancer), as well as describes the role of involved cytokines. Of note, there is a dual role of efferocytosis in the abovementioned disorders, and a paradoxical effect among non-tumor and tumor diseases in terms of inflammation resolution, immune response, and disease progression. Briefly, intact efferocytosis and cytokines promote tissue repair, while they contribute to tumor progression via the tumor microenvironment and macrophage politzerization. Additionally, this review provides potential targets associated with TAM (TYRO3, AXL, MERTK) receptors and cytokines, such as tumor necrosis factor α and CXCL5, suggesting potential novel therapeutic ways in treating diseases. Nearly 200–300 billion cells undergo turnover, and 0.4% of the estimated 37.2 trillion cells in an adult die every day.1Bianconi E. Piovesan A. Facchin F. Beraudi A. Casadei R. Frabetti F. Vitale L. Pelleri M.C. Tassani S. Piva F. et al.An estimation of the number of cells in the human body.Ann. Hum. Biol. 2013; 40: 463-471Crossref PubMed Scopus (614) Google Scholar,2Arandjelovic S. Ravichandran K.S. Phagocytosis of apoptotic cells in homeostasis.Nat. Immunol. 2015; 16: 907-917Crossref PubMed Scopus (541) Google Scholar During the homeostatic cell turnover, an immunologically non-inflammatory process, known as efferocytosis, is involved. Efferocytosis is a term derived from the Latin efferre, meaning to carry the dead to the grave. It describes the process by which apoptotic cells (ACs) are recognized and consumed by phagocytic cells, including professional phagocytes (e.g., macrophages and immature dendritic cells [DCs]) and nonprofessional phagocytes (e.g., epithelial and endothelial cells). Prompt clearance of ACs assists in preventing the leakage of intracellular contents that produce tissue inflammation, and to ensure that there is adequate space for young, healthy cells. Recent studies have identified the important role of efferocytosis in inflammation resolution, immune tolerance, cancer development, and tissue homeostasis. In addition, numerous studies have demonstrated that either intact or defective efferocytosis can have positive or negative effects on the body through various signals and released cytokines.3Morioka S. Maueröder C. Ravichandran K.S. Living on the edge: efferocytosis at the interface of homeostasis and pathology.Immunity. 2019; 50: 1149-1162Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar For example, in tumors such as breast cancer, efferocytosis influences the tumor microenvironment (TME) and facilitates tumor growth, while impaired efferocytosis increases secondary necrosis.4Vaught D.B. Stanford J.C. Cook R.S. Efferocytosis creates a tumor microenvironment supportive of tumor survival and metastasis.Cancer Cell Microenviron. 2015; 2: e666PubMed Google Scholar In brief, there is a dynamic balance of efferocytosis in the body, and a better understanding of efferocytosis may shed light on key pathophysiological processes. The process of efferocytosis involves the recruitment of phagocytic cells and the recognition, phagocytosis, and digestion of ACs. In these processes, signaling molecules could be divided into four types: find-me, eat-me, bridging, and don't eat-me signals (Figure 1). First, the find-me signals are exhibited in different forms, including nucleotides, proteins, lipids, and lipid products.5Gheibi Hayat S.M. Bianconi V. Pirro M. Sahebkar A. Efferocytosis: molecular mechanisms and pathophysiological perspectives.Immunol. Cell Biol. 2019; 97: 124-133Crossref PubMed Scopus (50) Google Scholar The best known types are the nucleotides, such as adenosine triphosphate (ATP) and uridine triphosphate (UTP). Released by ACs through pannexin 1, ATP/UTP can act as short-range chemoattractants to promote purinoreceptor-2-dependent recruitment of phagocytes.6Elliott M.R. Chekeni F.B. Trampont P.C. Lazarowski E.R. Kadl A. Walk S.F. Park D. Woodson R.I. Ostankovich M. Sharma P. et al.Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.Nature. 2009; 461: 282-286Crossref PubMed Scopus (1187) Google Scholar Other important contributors are proteins, such as fractalkine (CX3CL1), which is secreted from apoptotic lymphocytes and binds to its receptor (CX3CR1) on the surface of phagocytes to attract macrophages via caspase- and Bcl-2-regulated signals.7Truman L.A. Ford C.A. Pasikowska M. Pound J.D. Wilkinson S.J. Dumitriu I.E. Melville L. Melrose L.A. Ogden C.A. Nibbs R. et al.CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis.Blood. 2008; 112: 5026-5036Crossref PubMed Scopus (329) Google Scholar In addition, the lipid mediator, lysophosphatidylcholine, and the lipid product, sphingosine-1-phosphate (S1P), contribute to the recruitment of macrophages and the inhibition of necrosis.8Gude D.R. Alvarez S.E. Paugh S.W. Mitra P. Yu J. Griffiths R. Barbour S.E. Milstien S. Spiegel S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal.FASEB J. 2008; 22: 2629-2638Crossref PubMed Scopus (280) Google Scholar Particularly, the lysophosphatidylcholine and G protein-coupled receptor G2A system can attract phagocytes to ACs and prevent autoimmunity in a "keep calm" mechanism.9Peter C. Waibel M. Radu C.G. Yang L.V. Witte O.N. Schulze-Osthoff K. Wesselborg S. Lauber K. Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A.J. Biol. Chem. 2008; 283: 5296-5305Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar Second, eat-me signals are mainly composed of molecules on the surface of ACs, of which phosphatidylserine (PtdSer) is the most well-researched molecule. Eat-me signals also consist of modified molecules, such as intercellular adhesion molecule 3 and CD31. Normally, PtdSer is confined to the inner surface of the plasma membrane by the action of flippases that translocate PtdSer from the outer leaflet. When cells undergo apoptosis, PtdSer translocates to the cell surface due to the activation of scramblases and the inactivation of flippases.10Kawano M. Nagata S. Lupus-like autoimmune disease caused by a lack of Xkr8, a caspase-dependent phospholipid scramblase.Proc. Natl. Acad. Sci. USA. 2018; 115: 2132-2137Crossref PubMed Scopus (8) Google Scholar Later, the PtdSers on ACs are attached by PtdSer receptors on phagocytes, including T cell immunoglobulin mucin receptor 4 (TIM4) and TIM1, stabilins, and adhesion G protein-coupled receptor B1. ACs are engulfed and progress to the next stage. Third, bridging molecules are able to bind to both the ACs and the phagocytes with their receptor-binding domains. For instance, the molecules associated with PtdSer include growth arrest-specific 6 (GAS6), protein S (PROS1), and milk fat globule-epidermal growth factor 8 (MFG-E8),5Gheibi Hayat S.M. Bianconi V. Pirro M. Sahebkar A. Efferocytosis: molecular mechanisms and pathophysiological perspectives.Immunol. Cell Biol. 2019; 97: 124-133Crossref PubMed Scopus (50) Google Scholar,11Nishi C. Yanagihashi Y. Segawa K. Nagata S. MERTK tyrosine kinase receptor together with TIM4 phosphatidylserine receptor mediates distinct signal transduction pathways for efferocytosis and cell proliferation.J. Biol. Chem. 2019; 294: 7221-7230Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar as well as the TAM (TYRO3, AXL, MERTK) receptors and the αvβ3 and αvβ5 integrins.12Doran A.C. Yurdagul Jr., A. Tabas I. Efferocytosis in health and disease.Nat. Rev. Immunol. 2020; 20: 254-267Crossref PubMed Scopus (343) Google Scholar Specifically, MFG-E8 acts as a bridge linking ACs and macrophages via PtdSer and the αβ/β integrins to facilitate the tethering step, and then triggers a series of downstream signals to clear ACs.3Morioka S. Maueröder C. Ravichandran K.S. Living on the edge: efferocytosis at the interface of homeostasis and pathology.Immunity. 2019; 50: 1149-1162Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar,6Elliott M.R. Chekeni F.B. Trampont P.C. Lazarowski E.R. Kadl A. Walk S.F. Park D. Woodson R.I. Ostankovich M. Sharma P. et al.Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.Nature. 2009; 461: 282-286Crossref PubMed Scopus (1187) Google Scholar Fourth, don't eat-me signals usually exist on non-ACs, which prevents viable cells from being cleared by phagocytes. The best known don't eat-me signal is CD47. Although CD47 can protect normal cells, it renders malignant cells resistant to efferocytosis and promotes tumor progression, suggesting its contradictory role in efferocytosis. In conclusion, when apoptosis occurs, dying cells announce their presence to nearby phagocytes with find-me signals and then recruit motile phagocytes to the place of death. Meanwhile, ACs mark their outer leaflets with eat-me signals to allow themselves to be recognized by phagocytes. Eat-me signals are usually retained on the inner leaflets of the plasma membrane of healthy cells. Subsequently, phagocytes upregulate the corresponding cell surface receptors and bridging molecules to complete direct and indirect binding between the ACs and phagocytes.13Kumar S. Birge R.B. Efferocytosis.Curr. Biol. 2016; 26: R558-R559Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar After combination, the Crk II/Elmo-Dock180-Rac pathway is activated to promote cytoskeletal reorganization of phagocytes, leading to corpse internalization.14Albert M.L. Kim J.I. Birge R.B. αvβ5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells.Nat. Cell Biol. 2000; 2: 899-905Crossref PubMed Scopus (333) Google Scholar,15Kumar S. Calianese D. Birge R.B. Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment.Immunol. Rev. 2017; 280: 149-164Crossref PubMed Scopus (60) Google Scholar As a consequence (Figure 1), ACs are decomposed within the phagocytic cells by phagolysosomes. After digestion within the phagolysosome, cytokines are released, which further affects disease development (for details about molecules, see the reviews by Morioka et al.3Morioka S. Maueröder C. Ravichandran K.S. Living on the edge: efferocytosis at the interface of homeostasis and pathology.Immunity. 2019; 50: 1149-1162Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar and by Gheibi Hayat et al.5Gheibi Hayat S.M. Bianconi V. Pirro M. Sahebkar A. Efferocytosis: molecular mechanisms and pathophysiological perspectives.Immunol. Cell Biol. 2019; 97: 124-133Crossref PubMed Scopus (50) Google Scholar). Since efferocytosis involves the signals and corresponding cytokines mentioned above, proper regulation of the signals may enhance AC clearance, and drugs targeting special molecules may provide novel approaches to treat disorders. However, whether the effect of intact or impaired efferocytosis is beneficial for the body depends on the diseases, which is discussed as follows. Recently, a large number of studies have identified the role of efferocytosis in non-tumor and tumor diseases. The former primarily include atherosclerosis, lung diseases, and wounds, but the latter include breast cancer, prostate cancer (PCa), and leukemia. This section focuses on the relationships of efferocytosis and those diseases. The next section concentrates on the association between released cytokines during efferocytosis and these mentioned disorders. Although precise mechanisms relevant to efferocytosis among prevalent diseases are vague, researchers depict a relatively positive relationship between AC clearance and atherosclerosis, lung injury, and wound healing. When exposed to oxidized low-density lipoproteins (oxLDLs), there is a reduction of nitric oxide bioavailability, leading to endothelial activation and monocyte chemotaxis. This process then causes an accumulation of oxLDLs and differentiated macrophages, which generate an inflammatory stimulus within the subendothelial layer of arteries. Subsequently, excessive cholesterol accumulation induces transformation of lipid-laden phagocytes into foam cells, which eventually undergo apoptosis and necroptosis.16Otsuka F. Kramer M.C. Woudstra P. Yahagi K. Ladich E. Finn A.V. de Winter R.J. Kolodgie F.D. Wight T.N. Davis H.R. et al.Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: a pathology study.Atherosclerosis. 2015; 241: 772-782Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar,17Moore K.J. Sheedy F.J. Fisher E.A. Macrophages in atherosclerosis: a dynamic balance.Nat. Rev. Immunol. 2013; 13: 709-721Crossref PubMed Scopus (1708) Google Scholar Later, dying cells express eat-me molecules on their surface, such as calreticulin18Kojima Y. Downing K. Kundu R. Miller C. Dewey F. Lancero H. Raaz U. Perisic L. Hedin U. Schadt E. et al.Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis.J. Clin. Invest. 2014; 124: 1083-1097Crossref PubMed Scopus (105) Google Scholar and PtdSer. These molecules interact with the receptors (e.g., integrin αvβ5, MERTK, transglutaminase 2, low-density lipoprotein receptor-related protein 1 [LRP1], and scavenger receptor B) on phagocytes via bridging molecules, resulting in the activation of enzymes involved in phagolysosomal degradation and efferocytosis during early lesion formation.19Liu J. Thewke D.P. Su Y.R. Linton M.F. Fazio S. Sinensky M.S. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 174-179Crossref PubMed Scopus (186) Google Scholar, 20Arai 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. A role for the apoptosis inhibitory factor AIM/Spα/Api6 in atherosclerosis development.Cell Metab. 2005; 1: 201-213Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 21Babaev V.R. Ding L. Zhang Y. May J.M. Lin P.C. Fazio S. Linton M.F. Macrophage IKKα deficiency suppresses Akt phosphorylation, reduces cell survival, and decreases early atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 598-607Crossref PubMed Scopus (0) Google Scholar, 22Yurdagul Jr., A. Doran A.C. Cai B. Fredman G. Tabas I.A. Mechanisms and consequences of defective efferocytosis in atherosclerosis.Front. Cardiovasc. Med. 2018; 4: 86Crossref PubMed Google Scholar Efferocytosis also limits the progression of atherosclerosis via indirectly inhibiting the generation of reactive oxygen species (ROS) and pro-inflammatory mediators, and directly enhancing anti-inflammatory and anti-oxidant responses.23Lee H.N. Surh Y.J. Resolvin D1-mediated NOX2 inactivation rescues macrophages undertaking efferocytosis from oxidative stress-induced apoptosis.Biochem. Pharmacol. 2013; 86: 759-769Crossref PubMed Scopus (91) Google Scholar,24Noda M. Doi Y. Liang J. Kawanokuchi J. Sonobe Y. Takeuchi H. Mizuno T. Suzumura A. Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression.J. Biol. Chem. 2016; 291: 14388Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Although efferocytosis functions in early stages of atherosclerosis, its capabilities begin to wane in advanced plaques, and the necrotic core occurs after overproduction of secondarily necrotic cells.25Tabas I. Bornfeldt K.E. Macrophage phenotype and function in different stages of atherosclerosis.Circ. Res. 2016; 118: 653-667Crossref PubMed Scopus (693) Google Scholar In advanced plaques, the expressions of eat-me molecules and bridging molecules are decreased. However, increased tumor necrosis factor α (TNF-α) induces expression of the don't eat-me molecule CD47 via nuclear factor κB (NF-κB), ultimately rendering vascular cells resistant to efferocytosis.26Kojima Y. Volkmer J.P. McKenna K. Civelek M. Lusis A.J. Miller C.L. Direnzo D. Nanda V. Ye J. Connolly A.J. et al.CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.Nature. 2016; 536: 86-90Crossref PubMed Scopus (369) Google Scholar Moreover, Doran et al.12Doran A.C. Yurdagul Jr., A. Tabas I. Efferocytosis in health and disease.Nat. Rev. Immunol. 2020; 20: 254-267Crossref PubMed Scopus (343) Google Scholar drew a comprehensive and detailed relationship between advanced plaques and defective efferocytosis. One mechanism is linked to impaired efferocytosis in advanced atherosclerosis via the proteolytic cleavage of the key receptors, MERTK and LRP1, which increase plaque necrosis. Ait-Oufella et al.27Ait-Oufella H. Pouresmail V. Simon T. Blanc-Brude O. Kinugawa K. Merval R. Offenstadt G. Lesèche G. Cohen P.L. Tedgui A. Mallat Z. Defective Mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1429-1431Crossref PubMed Scopus (147) Google Scholar observed an accumulation of ACs and enhanced lesion development in low-density lipoprotein receptor-deficient female mice with MERTK deficiency after a high-fat diet. This is supported by Thorp et al.28Thorp E. Cui D. Schrijvers D.M. Kuriakose G. Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of Apoe−/− mice.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1421-1428Crossref PubMed Scopus (270) Google Scholar who found that mutation of the phagocytic MERTK receptor inhibits efferocytosis and accelerates the formation of necrotic plaques in Apoe−/− mice. Other researchers have suggested that protease disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) mediates the proteolysis of MERTK. Furthermore, the cleaved extracellular fragment named soluble MER can bind to GAS6, and thus suppress efferocytosis.29Thorp E. Vaisar T. Subramanian M. Mautner L. Blobel C. Tabas I. Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK).J. Biol. Chem. 2011; 286: 33335-33344Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Third, LRP1 may impair efferocytosis via exposure of macrophages to oxLDLs, or degradation by epsin-mediated and ubiquitin-dependent internalization.30Brophy M.L. Dong Y. Tao H. Yancey P.G. Song K. Zhang K. Wen A. Wu H. Lee Y. Malovichko M.V. et al.Myeloid-specific deletion of epsins 1 and 2 reduces atherosclerosis by preventing LRP-1 downregulation.Circ. 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The defective efferocytosis not only damages blood vessels, but it accelerates plaque necrosis through various mechanisms, such as MERTK cleavage and CD47 upregulation. These results indicate that improved efferocytosis and reduced oxLDLs in the early stages may significantly alleviate atherosclerosis. Although the process of efferocytosis shares many similarities with atherosclerosis, lung diseases have a closer relationship with efferocytosis. This is due to the greater number of phagocytic cell types (alveolar macrophages, lung DCs, epithelial cells, and fibroblasts) and disease types (asthma, cystic fibrosis, acute lung injury [ALI], and chronic obstructive pulmonary disease [COPD]) involved in this process besides the complex inflammatory and immune responses. Within AC clearance, alveolar macrophages possess multiple AC recognition receptors, such as TAM receptors and αvβ3 integrin.32Mohning M.P. Thomas S.M. Barthel L. Mould K.J. McCubbrey A.L. Frasch S.C. Bratton D.L. 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Cell Differ. 2017; 62: 299-313Crossref PubMed Scopus (62) Google Scholar To summarize, efferocytosis plays a significant role in maintaining lung homeostasis, and defective efferocytosis can cause acute and chronic lung injury due to extensive inflammation (Figure 2B). Nevertheless, the mechanism by which the phagocytic cells work together to have the utmost efficiency remains unknown. Furthermore, enhancers of efferocytosis, which could benefit patients with combined lung diseases, also remain unelucidated. These warrant thorough investigation to determine the extent of their potential in clinical use. Similar to the role of efferocytosis in atherosclerosis and lung diseases, efficient clearance of ACs and reduced inflammation contribute to wound healing. Generally, wound healing involves an intricate interplay between the immune system and phagocytic cells, which include four phases: hemostasis, inflammation, proliferation, and remodeling. During wound healing, there is an infiltration of abundant neutrophils. In addition, increased pro-inflammatory cytokines activate endothelial cells and platelets to exert protective effects.44Su Y. Richmond A. Chemokine regulation of neutrophil infiltration of skin wounds.Adv. Wound Care (New Rochelle). 2015; 4: 631-640Crossref PubMed Google Scholar Of note, the timely clearance of apoptotic neutrophils is quite important for allowing wound healing to enter into the proliferative phase from the inflammation phase.45Das A. Abas M. Biswas N. Banerjee P. Ghosh N. Rawat A. Khanna S. Roy S. Sen C.K. A modified collagen dressing induces transition of inflammatory to reparative phenotype of wound macrophages.Sci. Rep. 2019; 9: 14293Crossref PubMed Scopus (51) Google Scholar,46Gauthier A. Fisch A. Seuwen K. Baumgarten B. Ruffner H. Aebi A. Rausch M. Kiessling F. Bartneck M. 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