Platelets and the Complement Cascade in Atherosclerosis
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REVIEW ARTICLE published: 02 March 2015 doi: 10.3389/fphys.2015.00049 Platelets and the complement cascade in atherosclerosis Johannes Patzelt 1, Admar Verschoor 2* and Harald F. Langer 1,3* 1 University Clinic for Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany 2 Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany 3 Section for Cardioimmunology, Department of Cardiovascular Medicine, University of Tuebingen, Tuebingen, Germany Edited by: Atherosclerosis and its late sequels are still the number one cause of death in western Christian A. Gleissner, University of societies. Platelets are a driving force not only during the genesis of atherosclerosis, Heidelberg, Germany but especially in its late stages, as evidenced by complications such as arterial Reviewed by: thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly Klaus Ley, La Jolla Institute for Allergy and Immunology, USA recognized as an inflammatory disease, influenced by various immune mechanisms. Irena Levitan, University of Illinois at The complement system is part of our innate immune system, and its diverse roles Chicago, USA in atherosclerosis have become evident over the past years. In this review we identify *Correspondence: points of intersection between platelets and the complement system and discuss their Admar Verschoor, Institute for relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset Medical Microbiology, Immunology and Hygiene, Technische Universität as well as progression of the disease, a possible dual role for complement in the genesis München, Trogerstr. 30, 81675 and development of atherosclerosis, and review emerging literature revealing previously Munich, Germany unrecognized cross-talk between platelets and the complement system and discuss its e-mail: [email protected]; possible impact for atherosclerosis. Finally, we identify limitations of current research Harald F.Langer, Medizinische Klinik III, Kardiologie und approaches and discuss perspectives of complement modulation in the control of the Kreislauferkrankungen, Eberhard disease. Karls-Universität Tübingen, Otfried-Müllerstr. 10, 72076 Keywords: atherosclerosis, platelets, complement system proteins, innate immunity, inflammation Tübingen, Germany e-mail: harald.langer@ med.uni-tuebingen.de INTRODUCTION can also be a driving force behind the pathological processes Despite remarkable progress in therapy, atherosclerosis and its of chronic inflammatory diseases (Walport, 2001). The comple- associated complications such as coronary heart disease are still ment system consists of a series of plasmatic proteins (zymogens) the leading cause of death in western societies (Ross, 1999). that form enzymatic cascades, which produce a broad spectrum Atherosclerosis is defined as the process of plaque formation and of immune-active molecules and pro-inflammatory mediators stenosis in arterial vessels. Deleterious effects of plaque rupture (Verschoor and Carroll, 2004). Besides these classical functions include acute vessel occlusion and thromboembolic complica- of immune defense, the complement system also directs central tions such as myocardial infarction resulting from thrombotic homeostatic and pathophysiological processes such as angio- occlusion of an epicardial vessel or stroke resulting from carotid genesis, tissue regeneration, the removal of immune complexes, artery plaque formation. apoptotic cells, and cellular debris (Ricklin et al., 2010). Thus, A complex interplay between hemostatic and inflammatory with respect to atherosclerosis complement may exert proathero- cues is increasingly unraveled and recognized to drive the gene- genic as well as atheroprotective effects, for which we will discuss sis and exacerbations of atherosclerosis. Platelets are thought to the evidence below in detail. play a dual role here, mediating the often serious clinical effects of plaque rupture in established atherosclerosis, but also impact- PLATELETS AND ATHEROSCLEROSIS ing the early development of atherosclerosis (Massberg et al., Platelets have a well-recognized contribution to the late throm- 2002). The classical function of platelets is coverage and closure botic complications associated with atherosclerosis, making them of endothelial wounds, and contact between platelets and the a potent target for the development of diagnostic and therapeutic subendothelial matrix triggers their activation and drives throm- tools (Gawaz et al., 2008). In addition, platelets can also inter- bus formation also during the early pathophysiological process act with endothelial cells before an atherosclerotic plaque has of plaque formation (Figure 1). Moreover, platelets have been formed and may thus play a role in the genesis of atheroscle- shown to also interact with intact endothelium and recruit leuko- rosis (Gawaz et al., 2005). Indeed, platelets of atherosclerotic cytes even before an atherosclerotic plaque has formed (Massberg apolipoprotein E deficient (ApoE–/–) mice were observed to et al., 2002). adhere to intact endothelium via the von Willebrand factor On the other hand, atherosclerosis is recognized as an inflam- receptor GPIbα andthefibrinogenreceptorGPIIbIIIa well before matory disease (Ross, 1999), making the immune system a focus atherosclerotic plaques had formed (Massberg et al., 2002; Huo of interest. The complement system, as part of our immune sys- et al., 2003; Gawaz et al., 2005). Still, absence of GPIIbIIIa alone tem, has important protective functions in immune defense but does not fully protect from atherosclerosis, as is known from www.frontiersin.org March 2015 | Volume 6 | Article 49 | 1 Patzeltetal. Platelets, complement, atherosclerosis FIGURE 1 | Upper part: Model of platelet interaction with the damaged firm adhesion via β3 integrins. Interaction with endothelial bound vessel wall: exposure of subendothelial matrix after endothelial lesion chemokines such as Cx3CL1 (fractalkine) or CCL5 (Rantes) results in leads to platelet tethering, activation and accumulation to provide sealing P-Selectin mediated recruitment of leukocytes to the vessel wall and of the endothelial wound. Lower part: Model of platelet interaction with subsequent transmigration. For both interaction with the subendothelial the endothelium. Platelets interact with the endothelium via adhesion matix and the endothelium, major adhesion receptors expressed on receptors such as GPIbα and PSGL-1 promoting rolling and subsequent platelets are listed. studies assessing patients with Glanzmann thrombasthenia whose crucial steps in the initiation of atherosclerosis. Platelets express platelets lack functional GPIIbIIIa. Indeed, ultrasound imaging various inflammatory receptors, including fractalkine receptor of the carotid bifurcation of such patients revealed plaques in (CX3CR1) which induces P-selectin on platelets upon binding 4 of 7 individuals (Shpilberg et al., 2002). Therefore, platelet- to fractalkine (CX3CL1) expressed on inflamed endothelial cells vessel wall interactions via GPIIbIIIa may contribute to, but do not (Schulz et al., 2007). In turn, P-selectin exposure initiates local seem to be a prerequisite in the genesis of human atherosclerosis accumulation of leukocytes, driven by arterial shear forces (Schulz and may be functionally substituted by other platelet recep- et al., 2007)(Figure 1). The importance of P-selectin in the gen- tors. Mice with deficiency in GPIbα are not protected from esis of atherosclerosis is underlined by the finding of increased atherosclerotic plaque formation (Strassel et al., 2009). On the intima-media-thickness in human subjects presenting with high other hand, platelet depletion with a GPIbα-specifc antibody levels of platelet P-selectin (Koyama et al., 2003). Indeed, both in ApoE–/– mice leads to reduced leukocyte accumulation in platelet and endothelial P-selectin contributed to lesion forma- the arterial intima and attenuated atherosclerotic plaque for- tion in a mouse model of atherosclerosis that was based on mation, importantly indicating that adhering platelets form a the adoptive transfer of P-selectin positive or negative platelets focal point for the immune-cell driven inflammation that typ- (Burger and Wagner, 2003). ifies atherosclerosis (Massberg et al., 2002). Indeed, PSGL-1 or Whether platelet-adhesion to the intima mediates direct dam- GPIbα allow platelets to interact with P-selectin expressed on age to the endothelial lining remains unclear, but several studies intact endothelium. This initial “rolling” interaction is followed found how platelets contribute to vascular inflammation via their by β3 integrin–mediated firm “adhesion” of platelets to the interaction with leukocytes (Santoso et al., 2002; Schober et al., vessel wall (Gawaz et al., 2005), and these events are seen as 2002; Langer et al., 2007, 2012; Ley et al., 2007; Langer and Frontiers in Physiology | Vascular Physiology March2015|Volume6|Article49| 2 Patzeltetal. Platelets, complement, atherosclerosis Chavakis, 2009). Activated platelets were shown to exacerbate et al., 2002; Ferroni et al., 2006). In conclusion, platelet activation atherosclerosis in ApoE deficient mice via the recruitment of seems to confer proatherosclerotic effects, as well as effects of monocytes and other leukocytes (Wagner and Frenette, 2008; von atheromodulation and tissue/vascular remodeling. Hundelshausen et al., 2009). In turn, the formation of platelet- leukocyte aggregates (PLA) facilitated