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Annexin A2 in Inflammation and Host Defense

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Annexin A2 in Inflammation and Host Defense cells Review Annexin A2 in Inflammation and Host Defense Valentina Dallacasagrande and Katherine A. Hajjar * Department of Pediatrics, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; [email protected] * Correspondence: [email protected] Received: 31 May 2020; Accepted: 17 June 2020; Published: 19 June 2020 Abstract: Annexin A2 (AnxA2) is a multifunctional calcium2+ (Ca2+) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins underlies its role in regulating vascular integrity. In addition, its contribution to endosomal membrane repair impacts several aspects of inflammatory regulation, including lysosome repair, which regulates inflammasome activation, and autophagosome biogenesis, which is essential for macroautophagy. On the other hand, AnxA2 may be co-opted to promote adhesion, entry, and propagation of bacteria or viruses into host cells. In the later stages of acute inflammation, AnxA2 contributes to the initiation of angiogenesis, which promotes tissue repair, but, when dysregulated, may also accompany chronic inflammation. AnxA2 is overexpressed in malignancies, such as breast cancer and glioblastoma, and likely contributes to cancer progression in the context of an inflammatory microenvironment. We conclude that annexin AnxA2 normally fulfills a spectrum of anti-inflammatory functions in the setting of both acute and chronic inflammation but may contribute to disease states in settings of disordered homeostasis. Keywords: annexin A2; inflammation; infection; adherens junction; angiogenesis; macroautophagy 1. Introduction Inflammation is defined as the local host response to injury caused by infectious or noninfectious agents; it results in elimination or compartmentalization of the inciting agent, clearance of necrotic cells, and repair of damaged tissue [1,2]. Initially, host cells recognize danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) through germline-encoded pattern-recognition receptors (PRRs) expressed mainly in monocytes, macrophages, neutrophils, and dendritic cells [1]. The four known classes of PRR molecules include transmembrane proteins, such as Toll-like (TLRs) and C-type lectin receptors (CLRs), as well as cytoplasmic proteins, such as retinoic acid-inducible gene (RIG)-like receptors (RLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) [3]. These pathways induce the release of proinflammatory cytokines, which increase vascular permeability, thus facilitating the extravasation of immune cells into the damaged tissue, and chemokines, which recruit supplemental immune cells that phagocytose and kill pathogens [1]. Inflammation that resolves within days is classified as acute, whereas chronic inflammation may persist for months to years. Chronic inflammation underlies the pathogenesis of an array of disease entities, including diabetes, asthma, arthritis, cancer, atherosclerosis, vasculitis, and inflammatory bowel disease. The annexins are Ca2+-regulated, phospholipid- and membrane-binding proteins that are named after the Greek word “annex”, meaning to attach or bridge because of their ability to link membranes to other membranes or other structures [4]. All but one (A6) of the twelve annexin family members (A1–A11 and A13) identified in vertebrates have a highly homologous core domain (~30–35 kilodaltons) Cells 2020, 9, 1499; doi:10.3390/cells9061499 www.mdpi.com/journal/cells Cells 2020, 9, 1499 2 of 14 Cells 2020, 9, x FOR PEER REVIEW 2 of 14 kilodaltons),containing four which multi-alpha is specific helical for each repeats family with member potential [5,6]. CaThe2+ -bindingannexins activityare expressed and an ubiquitously N-terminal throughoutdomain (~3 the kilodaltons), phylogenetic which tree and is specific are evolutionarily for each family ancient. member [5,6]. The annexins are expressed ubiquitouslyAnnexin throughoutA2 (AnxA2) the is one phylogenetic of the most tree extensively and are evolutionarily studied members ancient. of the annexin superfamily [6]. AnxA2Annexin is produced A2 (AnxA2) by is a onewide of spectrum the most extensively of cell types, studied including members endothelial, of the annexin trophoblast, superfamily epithelial, [6]. andAnxA2 tumor is produced cells, as well by as a wide innate spectrum immune of cells, cell such types, as includingmacrophages, endothelial, monocytes, trophoblast, and dendritic epithelial, cells. AnxA2and tumor may cells, exist as in well either as innatemonomeric immune or heterotetrameric cells, such as macrophages, form. The heterotetramer monocytes, and (A2 dendriticS100A10) cells.2 isAnxA2 composed may existof two in copies either monomericeach of AnxA2 or heterotetrameric and protein S100A10, form. The also heterotetramer called p11. AnxA2 (A2 isS100A10) present inis • 2 thecomposed cytoplasm of two and copies on cell each surfaces, of AnxA2 and its and functions protein are S100A10, largely also location called specific. p11. AnxA2 On the is endothelial present in cellthe cytoplasmsurface, the and (A2 onS100A10) cell surfaces,2 complex and its binds functions components are largely of the location fibrinolytic specific. system, On the plasminogen endothelial andcell surface,tissue plasminogen the (A2 S100A10) activatorcomplex (tPA), accelerating binds components the activation of the of fibrinolytic the serine protease system, plasminogenplasmin [7,8]. • 2 Asand the tissue primary plasminogen fibrinolytic activator protease, (tPA), plasmin accelerating enables the activation fibrin breakdown of the serine and protease angiogenesis plasmin [9,10]. [7,8]. Intracellularly,As the primary AnxA2 fibrinolytic seems protease, to fulfill plasmin many enablesfunctions, fibrin including breakdown organization and angiogenesis of specialized [9,10]. membraneIntracellularly, microdomains, AnxA2 seems facilitation to fulfill many of vesicle functions, budding, including and organization regulation of of additional specialized membrane membrane dynamicmicrodomains, events facilitation such as fusion, of vesicle endocytosis, budding, endosomal and regulation biogenesis, of additional and membrane membrane repair dynamic [4,5,11–21]. events suchIn as view fusion, of endocytosis, this wide array endosomal of functions, biogenesis, we have and membranedeveloped repaira working [4,5,11 model–21]. depicting the disparateIn view anti of‐ thisand wide pro‐inflammatory array of functions, roles we of have AnxA2 developed at the various a working stages model of depictinginflammation the disparate (Figure 1).anti- In and the pro-inflammatoryinitial phase, AnxA2 roles limits of AnxA2 vascular at the permeability, various stages thereby of inflammation modulating (Figure recruitment1). In the of leukocytesinitial phase, and AnxA2 their limitssubsequent vascular release permeability, of inflammatory thereby modulatingmediators. AnxA2 recruitment also supports of leukocytes internal and membranetheir subsequent repair, release thus modulating of inflammatory inflammasome mediators. activation, AnxA2 also and supports participates internal in membranethe biogenesis repair, of thethus phagophore modulating in inflammasome autophagy, thereby activation, facilitating and participates the removal in of thepathogens biogenesis and of damaged the phagophore organelles. in Later,autophagy, AnxA2 thereby enables facilitating angiogenesis the removal and tissue of pathogens healing. and damaged organelles. Later, AnxA2 enables angiogenesis and tissue healing. Figure 1. Annexin A2 in inflammatory responses—working model. Under homeostatic conditions (top arrow), AnxA2 plays an anti-inflammatory role in response to injury or infection. In the immediate response to injury, AnxA2 maintains vascular integrity, thereby preventing edema and extravasation Figureof 1. blood Annexin cells. A2 Within in inflammatory minutes to responses—working hours, AnxA2 also protects model. Under internal homeostatic membranes, conditions such as those (top arrow),delimiting AnxA2 theplays lysosome, an anti thus‐inflammatory preventing inflammasomerole in response activation to injury and or tempering infection. cytokine In the production.immediate responseAnxA2 to injury, is also AnxA2 necessary maintains for biogenesis vascular of theintegrity, phagophore, thereby a doublepreventing membrane edema structureand extravasation that engulfs of bloodand cells. destroys Within intracellularminutes to hours, pathogens AnxA2 and also allows protects the internal cell to adapt membranes, to environmental such as those stresses delimiting in the the lysosome,process of thus macroautophagy. preventing inflammasome In the later stagesactivation of inflammation, and tempering AnxA2 cytokine likely production. promotes AnxA2 angiogenesis is also necessaryand woundfor biogenesis healing byof supportingthe phagophore, cell surface a double fibrinolytic membrane activity. structure In disease that states, engulfs however and destroys (bottom intracellulararrow), pathogens AnxA2 may and be co-optedallows the to performcell to pro-inflammatoryadapt to environmental actions. stresses On the plasmain the membrane,process of macroautophagy.AnxA2 appears In tothe serve later as stages a site for of bacterial inflammation, adhesion AnxA2 and entry likely into promotes cells, and angiogenesis may enable viral and infection, wound healingreplication, by supporting and release.
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