Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis

Overview

Journal Front Cardiovasc Med

Specialty Cardiology & Vascular Diseases

Date 2018 Jan 31

PMID 29379788

Citations 132

Authors

Arif Yurdagul Jr

Amanda C Doran

Bishuang Cai

Gabrielle Fredman

Ira A Tabas

Affiliations

Soon will be listed here.

Abstract

Efficient clearance of apoptotic cells, termed efferocytosis, critically regulates normal homeostasis whereas defective uptake of apoptotic cells results in chronic and non-resolving inflammatory diseases, such as advanced atherosclerosis. Monocyte-derived macrophages recruited into developing atherosclerotic lesions initially display efficient efferocytosis and temper inflammatory responses, processes that restrict plaque progression. However, during the course of plaque development, macrophages undergo cellular reprogramming that reduces efferocytic capacity, which results in post-apoptotic necrosis of apoptotic cells and inflammation. Furthermore, defective efferocytosis in advanced atherosclerosis is a major driver of necrotic core formation, which can trigger plaque rupture and acute thrombotic cardiovascular events. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis, how efferocytosis promotes the resolution of inflammation, and how defective efferocytosis leads to the formation of clinically dangerous atherosclerotic plaques.

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References

Schrijvers D, De Meyer G, Kockx M, Herman A, Martinet W . Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25(6):1256-61. DOI: 10.1161/01.ATV.0000166517.18801.a7. View

Shen Z, Chen X, Sun X, Sun J, Zhang W, Zheng X . Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis. J Biol Chem. 2016; 292(3):925-935. PMC: 5247664. DOI: 10.1074/jbc.M116.739243. View

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885):182-7. DOI: 10.1038/417182a. View

Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y . Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature. 2006; 443(7114):998-1002. DOI: 10.1038/nature05245. View

Tabas I . Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005; 25(11):2255-64. DOI: 10.1161/01.ATV.0000184783.04864.9f. View

Tabas I . Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2009; 10(1):36-46. PMC: 2854623. DOI: 10.1038/nri2675. View

Brown S, Heinisch I, Ross E, Shaw K, Buckley C, Savill J . Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature. 2002; 418(6894):200-3. DOI: 10.1038/nature00811. View

Cai B, Thorp E, Doran A, Subramanian M, Sansbury B, Lin C . MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A. 2016; 113(23):6526-31. PMC: 4988577. DOI: 10.1073/pnas.1524292113. View

Aprahamian T, Rifkin I, Bonegio R, Hugel B, Freyssinet J, Sato K . Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med. 2004; 199(8):1121-31. PMC: 2211887. DOI: 10.1084/jem.20031557. View

10.

A-Gonzalez N, Bensinger S, Hong C, Beceiro S, Bradley M, Zelcer N . Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009; 31(2):245-58. PMC: 2791787. DOI: 10.1016/j.immuni.2009.06.018. View

11.

Yahagi K, Kolodgie F, Otsuka F, Finn A, Davis H, Joner M . Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol. 2015; 13(2):79-98. DOI: 10.1038/nrcardio.2015.164. View

12.

Subramanian M, Proto J, Matsushima G, Tabas I . Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression. Sci Rep. 2016; 6:39111. PMC: 5153620. DOI: 10.1038/srep39111. View

13.

Truman L, Ford C, Pasikowska M, Pound J, Wilkinson S, Dumitriu I . CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008; 112(13):5026-36. DOI: 10.1182/blood-2008-06-162404. View

14.

Serhan C . Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014; 510(7503):92-101. PMC: 4263681. DOI: 10.1038/nature13479. View

15.

Yurdagul Jr A, Sulzmaier F, Chen X, Pattillo C, Schlaepfer D, Orr A . Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression. J Cell Sci. 2016; 129(8):1580-91. PMC: 4852771. DOI: 10.1242/jcs.182097. View

16.

Gorovoy M, Gaultier A, Campana W, Firestein G, Gonias S . Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages. J Leukoc Biol. 2010; 88(4):769-78. PMC: 2974427. DOI: 10.1189/jlb.0410220. View

17.

Yancey P, Blakemore J, Ding L, Fan D, Overton C, Zhang Y . Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler Thromb Vasc Biol. 2010; 30(4):787-95. PMC: 2845445. DOI: 10.1161/ATVBAHA.109.202051. View

18.

Li W . Eat-me signals: keys to molecular phagocyte biology and "appetite" control. J Cell Physiol. 2011; 227(4):1291-7. PMC: 3242927. DOI: 10.1002/jcp.22815. View

19.

Kusters D, Chatrou M, Willems B, De Saint-Hubert M, Bauwens M, van der Vorst E . Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet. PLoS One. 2015; 10(6):e0130484. PMC: 4475013. DOI: 10.1371/journal.pone.0130484. View

20.

Segawa K, Suzuki J, Nagata S . Constitutive exposure of phosphatidylserine on viable cells. Proc Natl Acad Sci U S A. 2011; 108(48):19246-51. PMC: 3228483. DOI: 10.1073/pnas.1114799108. View