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The Inflammatory Role of Platelets via Their TLRs and Siglec Receptors

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      Abstract

      Platelets are non-nucleated cells that play central roles in the processes of hemostasis, innate immunity, and inflammation; however, several reports show that these distinct functions are more closely linked than initially thought. Platelets express numerous receptors and contain hundreds of secretory products. These receptors and secretory products are instrumental to the platelet functional responses. The capacity of platelets to secrete copious amounts of cytokines, chemokines, and related molecules appears intimately related to the role of the platelet in inflammation. Platelets exhibit non-self-infectious danger detection molecules on their surfaces, including those belonging to the “toll-like receptor” family, as well as pathogen sensors of other natures (Ig- or complement receptors, etc.). These receptors permit platelets to both bind infectious agents and deliver differential signals leading to the secretion of cytokines/chemokines, under the control of specific intracellular regulatory pathways. In contrast, dysfunctional receptors or dysregulation of the intracellular pathway may increase the susceptibility to pathological inflammation. Physiological vs. pathological inflammation is tightly controlled by the sensors of danger expressed in resting, as well as in activated, platelets. These sensors, referred to as pathogen recognition receptors, primarily sense danger signals termed pathogen associated molecular patterns. As platelets are found in inflamed tissues and are involved in auto-immune disorders, it is possible that they can also be stimulated by internal pathogens. In such cases, platelets can also sense danger signals using damage associated molecular patterns (DAMPs). Some of the most significant DAMP family members are the alarmins, to which the Siglec family of molecules belongs. This review examines the role of platelets in anti-infection immunity via their TLRs and Siglec receptors.

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      Most cited references 158

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      Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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        The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.

        The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
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          A Toll-like receptor recognizes bacterial DNA.

           T Kawai,  S. Sato,  H Hemmi (2000)
          DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.
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            Author and article information

            Affiliations
            1Etablissement Français du Sang Auvergne-Loire , Saint-Etienne, France
            2GIMAP-EA3064, Université de Lyon , Saint Etienne, France
            3Faculty of Health Sciences, Colleges of Pharmacy and Medicine, University of Manitoba , Winnipeg, MB, Canada
            4Institut National de Transfusion Sanguine (INTS) , Paris, France
            Author notes

            Edited by: Heiko Mühl, University Hospital Goethe University Frankfurt, Germany

            Reviewed by: Patrizia Rovere Querini, Ospedale San Raffaele and Vita-Salute University, Italy; Matthew Dean Linden, University of Western Australia, Australia

            *Correspondence: Fabrice Cognasse, GIMAP-EA 3064, Faculté de Médecine, Université de Saint-Etienne, 15 rue Ambroise Paré, 42023 Saint-Etienne Cedex 2, France; Etablissement Français du Sang Auvergne-Loire, 25 Boulevard Pasteur, Saint-Etienne 42100, France e-mail: fabrice.cognasse@ 123456efs.sante.fr

            This article was submitted to Inflammation, a section of the journal Frontiers in Immunology.

            Contributors
            Journal
            Front Immunol
            Front Immunol
            Front. Immunol.
            Frontiers in Immunology
            Frontiers Media S.A.
            1664-3224
            02 March 2015
            2015
            : 6
            4345914 10.3389/fimmu.2015.00083
            Copyright © 2015 Cognasse, Nguyen, Damien, McNicol, Pozzetto, Hamzeh-Cognasse and Garraud.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 4, Tables: 3, Equations: 0, References: 157, Pages: 15, Words: 12471
            Funding
            Funded by: French National Blood Service – EFS (Grant APR), France
            Funded by: Association for Research in Transfusion (ART), Paris, France
            Funded by: Agence Nationale de la Sécurité et du Médicament et des produits de santé
            Award ID: ANSM – AAP-2012-011
            Award ID: 2012S055
            Funded by: “Agence Nationale de la Recherche” (ANR)
            Award ID: ANR-12-JSV1-0012-01
            Funded by: Association “Les Amis de Rémi,” Savigneux, France
            Categories
            Immunology
            Review Article

            Immunology

            siglec, platelets, tlr, inflammation, cytokine/chemokine, innate immunity

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