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Biomolecules biomolecules Review High-Density Lipoproteins Are Bug Scavengers Olivier Meilhac 1,2,*, Sébastien Tanaka 1,3 and David Couret 1,4 1 Université de la Réunion, Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; [email protected] (S.T.); [email protected] (D.C.) 2 CHU de La Réunion, Centre d’Investigations Clinique 1410, 97410 Saint-Pierre, France 3 AP-HP, Service d’Anesthésie-Réanimation, CHU Bichat-Claude Bernard, 75018 Paris, France 4 CHU de La Réunion, Neurocritical Care Unit, 97410 Saint-Pierre, France * Correspondence: [email protected]; Tel.: +33-262-93-88-11 Received: 7 March 2020; Accepted: 6 April 2020; Published: 12 April 2020 Abstract: Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol transporter could be challenged. All lipoproteins are reported to bind and potentially neutralize bacterial lipopolysaccharides (LPS); this is particularly true for HDL particles. In addition, HDL levels are drastically decreased under infectious conditions such as sepsis, suggesting a potential role in the clearance of bacterial material and, particularly, LPS. Moreover, “omics” technologies have unveiled significant changes in HDL composition in different inflammatory states, ranging from acute inflammation occurring during septic shock to low-grade inflammation associated with moderate endotoxemia such as periodontal disease or obesity. In this review, we will discuss HDL modifications associated with exposure to pathogens including bacteria, viruses and parasites, with a special focus on sepsis and the potential of HDL therapy in this context. Low-grade inflammation associated with atherosclerosis, periodontitis or metabolic syndrome may also highlight the protective role of HDLs in theses pathologies by other mechanisms than the reverse transport of cholesterol. Keywords: sepsis; periodontal disease; obesity; atherosclerosis; lipopolysaccharide; bacteria; virus; parasite; arthropods; HDL therapy 1. Introduction High-density lipoproteins (HDLs) are regarded as cholesterol transporters in charge of reverse cholesterol transport from tissues back to the liver. They are associated with reduced risk of developing cardiovascular clinical complications, notably since the publication of the Framingham study, concluding that low HDL-cholesterol (HDL-C) levels were as much a risk factor for coronary artery disease (CAD) as high LDL-C [1]. However, HDL-C-raising therapies all failed at improving cardiovascular outcome, such as cholesteryl ester-transfer protein (CETP) inhibitors, which were very disappointing in phase III trials, for which the conclusion was “insufficient cardiovascular benefit for routine use” [2]. Supplementation therapies relying on an infusion of reconstituted HDLs did not significantly impact on atherosclerotic plaque regression [3] and still need to prove that they could be beneficial in reducing cardiovascular events [4]. In addition, recent Mendelian studies challenged the causal role of low HDL-C levels in cardiovascular diseases (CVD) [5]. In this context, HDL research in CVD resulted less attractive and is currently somehow abandoned. Old concepts have reemerged, coming from different medical specialties—in particular, from the infectious field. Rather than HDL-cholesterol concentration, HDL functionality is a parameter that should be evaluated Biomolecules 2020, 10, 598; doi:10.3390/biom10040598 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 598 2 of 18 as these lipoproteins display pleiotropic effects and may be modulated under pathological conditions. In this review, we will address the possible involvement of HDLs in infectious diseases, as well as their potential for therapeutic applications. 2. HDLs and Innate Immunity: From Arthropods to Vertebrates From an evolutionary point of view, lipoproteins are not only described as lipid transporters but also display important functions in many aspects of immunity. Invertebrate species have an open circulatory system called hemolymph, and their primary defense against microbial invasion may be related to circulating apolipoproteins in the first place and, then, by the activation of the coagulation system in response to a breach of their exoskeleton by either trauma or infection [6]. In Galleria mellonella (greater wax moth), the apolipoprotein III (also called apolipophorin III) has been reported to play an important role in immunity [7], acting as a pathogen recognition receptor stimulating the activity of defense peptides and shown to possess antimicrobial activity [8,9]. These properties have also been reported in the Chinese oak silkworm Antheraea pernyi [10]. In both vertebrates and arthropods, thrombus formation represents a basic mechanism of defense, allowing the trapping of whole bacteria or bacterial components such as LPS released from Gram-negative bacteria, flagellin, peptidoglycan or DNA unmethylated CpG motifs in order to limit their systemic dispersal [6,11]. Lipoproteins, and in particular, HDLs may play an important role in the case of a low-grade infection by enhancing the clearance of circulating bacterial material in order to limit thrombus formation to endothelial breaches (Figure1). HDLs have been shown to display anticoagulant activity via enhancement of activated protein C/protein S [12]. Indeed, HDL levels are decreased in patients with venous thrombosis [13]. In addition to their direct action on the coagulation cascade, HDLs may also limit the prothrombotic effect of overactivated neutrophils. In response to LPS, neutrophils were shown to expel their DNA, forming a net that traps bactericidal proteins such as elastase, cathepsin G or histones aimed at limiting the spreading of bacteria [14]. These NETs (for neutrophil extracellular traps) also promote the formation of a thrombus [15] in collaboration with platelets via their Toll-like receptor 4 (TLR-4) [16] in order to confine bacteria. HDLs may then counterbalance the effect of neutrophils in case of bacteremia by quenching LPS and also by a direct action on neutrophil activation. Indeed, HDLs have been shown to limit neutrophil respiratory bursts [17] and subsequent activations—in particular, the release of myeloperoxidase and elastase in ischemic conditions [18] and in the context of atherosclerosis both in vitro and in vivo [19]. In this latter study, Murphy et al. reported that an infusion of reconstituted HDLs in patients with peripheral vascular disease presented a significantly attenuated neutrophil activation. Finally, HDLs may also modulate directly or indirectly platelet activation by limiting intraplatelet cholesterol overload or via their potential to increase NO and prostacyclin production by endothelial cells (potent inhibitors of platelet activation) [20]. Biomolecules 2020, 10, 598 3 of 18 Biomolecules 2020, 10, x 3 of 18 Figure 1. Role of high-density lipoproteins (HDLs) in the modulation of bacterial neutrophil Figure 1. Role of high-density lipoproteins (HDLs) in the modulation of bacterial neutrophil activation. activation. HDLs are able to bind and neutralize both lipoteichoic acid (LTA) [21] from Gram-positive HDLs are able to bind and neutralize both lipoteichoic acid (LTA) [21] from Gram-positive bacteria bacteria and lipopolysaccharides (LPS) from Gram-negative bacteria via the action of the andphospholipid lipopolysaccharides transfer (LPS)protein from (PLTP) Gram-negative (1). These two bacteria bacterial via thecomponents action of theare phospholipidpotent activators transfer of proteinneutrophil (PLTP) activation, (1). These potentially two bacterial leading components to the formation are potent of neutrophil activators extracellular of neutrophil traps activation,(NETs). potentiallyNETs consist leading in the to theextrusion formation of their of neutrophil nuclear content extracellular (DNA and traps histones), (NETs). which NETs forms consist a innet the extrusionassociated of their with nucleardifferent content proteins (DNA contained and histones),in neutrophil which granules forms (such a net as associated myeloperoxidase with di ffanderent proteinselastase). contained HDLs may in neutrophil also inhibitgranules directly the (such oxidative as myeloperoxidase burst (2) [22], leading and elastase). to neutrophil HDLs activation may also inhibitand directlysubsequent the release oxidative of their burst granule (2) [22 content.], leading A tomoderate neutrophil neutrophil activation activation and subsequent may be induced release of theirby LPS granule or bacterial content. phagocytosis A moderate without neutrophil the formation activation of NETs. may In this be case, induced HDLs by may LPS be orsufficient bacterial phagocytosisto promote withoutthe clearance the formationof bacteria/bacterial of NETs. material In this (3) case, via the HDLs liver may and besubsequent sufficient bile to elimination promote the clearance(systemic of phase). bacteria In/bacterial these low-grade material inflammatory (3) via the conditions, liver and subsequent ApoA1 may bilebe oxidized elimination by MPO (systemic and phase).produce In these dysfunctional low-grade HDL inflammatory particles (oxHDL) conditions, [23,24]. ApoA1 HDLs maymay bealso oxidized limit NET by formation MPO and via produce the dysfunctionalaction
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