The word thromboinflammation appeared in 2004 to describe the interactions and cooperation between platelets and neutrophils in the context of arterial in-stent restenosis (1). Almost two decades later, multiple sources of evidence clearly show that the interplay between thrombosis and inflammation involves several pathways and occurs in various pathophysiological situations such as sepsis, disseminated intravascular coagulation (DIC), stroke, cancer, stress and rheumatoid arthritis, among others. Thromboinflammation is driven by mutual interactions and reciprocal activation between endothelial cells, subendothelium, leukocytes, platelets, and the humoral innate immune system, involving the complement, coagulation, and fibrinolytic signaling cascades.Fil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Jenne, Craig N.. University of Calgary; CanadáFil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ho-Tin-Noe, Benoit. Universite de Paris; Franci

Ho-Tin-Noe, Benoit

Jenne, Craig N.

Negrotto, Soledad

Schattner, Mirta Ana

Frontiers in Immunology

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EDITORIALpublished: 28 May 2020doi: 10.3389/fimmu.2020.01079Frontiers in Immunology | www.frontiersin.org 1 May 2020 | Volume 11 | Article 1079Edited and reviewed by:Francesca Granucci,University of Milano-Bicocca, Italy*Correspondence:Mirta Schattnermschattner@hematologia.anm.edu.ar†These authors have contributedequally to this workSpecialty section:This article was submitted toMolecular Innate Immunity,a section of the journalFrontiers in ImmunologyReceived: 15 April 2020Accepted: 05 May 2020Published: 28 May 2020Citation:Schattner M, Jenne CN, Negrotto Sand Ho-Tin-Noe B (2020) Editorial:Platelets and Immune ResponsesDuring Thromboinflammation.Front. Immunol. 11:1079.doi: 10.3389/fimmu.2020.01079Editorial: Platelets and ImmuneResponses DuringThromboinflammationMirta Schattner 1*†, Craig N. Jenne 2†, Soledad Negrotto 1† and Benoit Ho-Tin-Noe 3†1 Laboratory of Experimental Thrombosis, Institute of Experimental Medicine-CONICET-National Academy of Medicine,Buenos Aires, Argentina, 2Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary,AB, Canada, 3Université de Paris, LVTS, Inserm U1148, Paris, FranceKeywords: platelets, thromboinflammation, neutrophils, endothelial cells, inflammation, sepsis, cancerEditorial on the Research TopicPlatelets and Immune Responses During ThromboinflammationThe word thromboinflammation appeared in 2004 to describe the interactions and cooperationbetween platelets and neutrophils in the context of arterial in-stent restenosis (1). Almost twodecades later, multiple sources of evidence clearly show that the interplay between thrombosisand inflammation involves several pathways and occurs in various pathophysiological situationssuch as sepsis, disseminated intravascular coagulation (DIC), stroke, cancer, stress and rheumatoidarthritis, among others. Thromboinflammation is driven by mutual interactions and reciprocalactivation between endothelial cells, subendothelium, leukocytes, platelets, and the humoral innateimmune system, involving the complement, coagulation, and fibrinolytic signaling cascades.In many respects, this linkage between inflammation and thrombosis is not entirely surprising.Some of the earliest examples of innate immunity center on the use of “clotting” or “coagulation”to respond to infectious agents and tissue damage. In some invertebrates, this “clotting” responseoccurs in the hemolymph and is facilitated by hemocytes, the evolutionary ancestor to thevertebrate platelet (2). In these systems, exposure of hemocytes, or hemolymph to bacteria resultsin rapid coagulation of the hemolymph, trapping the pathogen, and limiting its dissemination(3). This early basic response has evolved to become more specialized, creating distinct roles ofhemostasis, inflammation, and immunity; however, the evolutionary overlap in these processesremain and continue to play a role in a wide variety of pathophysiological conditions andhuman disease.In this Special Research Topic issue on the recent advances in Thromboinflammation,we compiled 15 reviews and one original article which provide comprehensive basic, andclinical insights on the current view of thromboinflammation. These articles also addressthe development and use of novel therapeutics in both experimental settings as well as inclinical trials, moving our understanding of the topic forward within the context of treatinghuman disease.Long before the term thromboinflammation was coined, interactions between neutrophils andplatelets had been suspected to play a pathophysiological role in both myocardial and cerebralischemia-reperfusion injury (4–7). Schanze et al. and Stegner et al. present early and recent findingson the crucial contribution of platelets to the course of ischemia-reperfusion injury and discuss howour current understanding of the underlyingmolecular mechanisms could translate into the clinics.A particular focus on the role of the vonWillebrand factor (VWF)/glycoprotein Ibα (GPIbα) axis inthe thromboinflammatory response during ischemic stroke is given by Denorme et al.. This workexplores the “thrombo-inflammatory” environment surrounding VWF-platelet interactions withinSchattner et al. Platelets and Immunity During Thromboinflammationthe context of cardiovascular diseases and how theseplayers may serve as both important clinical markers ofdisease and also key therapeutic targets for the treatment ofstroke patients.Recent years have seen a growing interest for the impactof the gut microbiome on the development of diseaseswith an immune and/or thrombotic component, suchas cardiovascular diseases. In this context, Bayer et al.,highlight the fact that antibiotics-based protocols commonlyused in this research field can significantly alter hostphysiology, notably by impacting the cardiovascular systemand the actors of the thromboinflammatory cascade. Theauthors emphasize the importance of instead consideringthe use of germ-free mouse models, which remain thestate-of-the-art approach for studying host-microbe andmicrobe-microbe interactions.Beyond cardiovascular health, inflammation is oftenassociated with the development and progression of cancer.Emerging in this field is the view that considers malignanttumors as wounds that do not heal. In this scenario, plateletsare intimately involved in the vicious circle of activatingcancer cells which, in turn, activate platelets. This mutual cellactivation can ultimately end in the well-recognized cancer-associated thrombosis or can further fuel the inflammatorymicroenvironment which favors tumor growth and metastasis.Palacios-Acedo et al. give a detailed description of the moleculesand mechanisms in these events, while Marin Oyarzúnand Heller summarize current knowledge about the roleof platelets in the thrombotic complications of chronicmyeloproliferative neoplasms.The crossroad of inflammation and thrombosis is very well-exemplified during envenomation. Several characterized proteinsin particular from viper snake venoms can activate the innateimmune and/or hemostasis systems. Teixeira et al. offer andextended review of these molecules and its mechanisms ofaction in this elaborate interplay between predator venom andhost hematology.Platelets and coagulation are often centrally involved in thehost response to infectious disease as well. Manifestations ofdysregulated coagulation, such as DIC, are frequently associatedwith the systemic immune response, such as in the case of sepsis,and are almost invariantly linked to worse patient outcomes.In this issue, reviews by Kerrigan et al. and by McDonald andDunbar explore how this dysregulated response is initiated inthe septic patient and how its manifestation impacts both theinfection itself (protective) and vascular health (pathogenic). Ina complementary review, Assinger et al. give a timely update onexperimental models of sepsis, highlighting both the interest andlimitations of animal models to study platelet-related functionsin sepsis.Additional contributions address the role of the platelet asan immune sentinel, detecting and initiating the response toinfection. Guo and Rondina address the broad ability of plateletsto respond to Pathogen Associated Molecular Patterns (PAMPs),complement and antibodies and how activated platelets in turndrive and modulate the host immune response. The authorsalso address how this host immune response is intimatelyintertwined with both the hemostatic and thrombotic pathways,directly impacting patient outcomes in infectious disease.Ramirez et al. build on this theme, shedding light on thedirect interplay between platelets and neutrophils within thecontext of chronic inflammation. Importantly, this work alsoaddresses both platelet production within the bone marrow ofpatients with chronic disease and the role of platelet-derivedmicroparticles within chronic inflammation. The role of theplatelet as an innate immune cell is further discussed in thereview by Eriksson et al., in which the interactions betweenactivated platelets and the complement system, as well astheir clinical implications, are thoroughly presented. Cognasseet al. broaden our perspective of the immunomodulatoryproperties of platelets by presenting how platelets can themselvesrelease non-infectious danger signals during storage of plateletconcentrates, thus contributing to adverse immune reactions toplatelet transfusion.Additionally, a review by Mezger et al. gives anoverview of several non-hemostatic functions of platelets,including the regulation of angiogenesis, tissue remodeling,and other processes contributing to the progression ofvarious thromboinflammatory conditions like cancers andcardiovascular diseases.Finally, in an original article and by using a pre-establishedmouse model of oral acute Chagas disease, Antunes et al.demonstrate for the first time that Trypanosoma cruziinfection leads to a decrease in platelet count, increasedbleeding and coagulation time, host responses that correspondto the peak of parasitemia. Importantly, circulating IL-6levels seem to be involved in these hematological changesduring oral Trypanosoma cruzi infection. These data mayhelp elucidate the mechanism of oral acute Chagas diseasepathogenesis and provide additional insight on the interactionbetween inflammation and coagulation in the context ofinfectious diseases.Overall, this collection of manuscripts expands ourunderstanding of the non-hemostatic roles of platelets,highlighting the central role thrombocytes play inlinking coagulation, inflammation, and immunity byparticipating in a spectrum of immunothromboticresponses and directly impacting host responses anddisease outcomes.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.ACKNOWLEDGMENTSWe wish to convey our appreciation to all the authors who haveparticipated in this Research Topic and the reviewers for theirinsightful comments.Frontiers in Immunology | www.frontiersin.org 2 May 2020 | Volume 11 | Article 1079Schattner et al. Platelets and Immunity During ThromboinflammationREFERENCES1. Tanguay JF, Geoffroy P, Dorval JF, Sirois MG. Percutaneous endoluminalarterial cryoenergy improves vascular remodelling after angioplasty. ThrombHaemost. (2004) 92:1114–21. doi: 10.1160/TH04-06-03362. Jiravanichpaisal P, Lee BL, Soderhall K. Cell-mediated immunity in arthropods:hematopoiesis, coagulation, melanization and opsonization. Immunobiology.(2006) 211:213–36. doi: 10.1016/j.imbio.2005.10.0153. Iwanaga S, Lee BL. Recent advances in the innate immunityof invertebrate animals. J Biochem Mol Biol. (2005) 38:128–50.doi: 10.5483/BMBRep.2005.38.2.1284. Romson JL, Hook BG, Rigot VH, Schork MA, Swanson DP,Lucchesi BR. The effect of ibuprofen on accumulation of indium-111-labeled platelets and leukocytes in experimental myocardialinfarction. Circulation. (1982) 66:1002–11. doi: 10.1161/01.CIR.66.5.10025. Bednar M, Smith B, Pinto A, Mullane KM. Neutrophil depletion suppresses111In-labeled platelet accumulation in infarcted myocardium. J CardiovascPharmacol. (1985) 7:906–12. doi: 10.1097/00005344-198509000-000146. Del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM.Polymorphonuclear leukocytes occlude capillaries following middle cerebralartery occlusion and reperfusion in baboons. Stroke. (1991) 22:1276–83.doi: 10.1161/01.STR.22.10.12767. Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, Del Zoppo GJ. Influx ofleukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol.(1994) 144:188–99.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2020 Schattner, Jenne, Negrotto and Ho-Tin-Noe. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Immunology | www.frontiersin.org 3 May 2020 | Volume 11 | Article 1079

Editorial: Platelets and Immune Responses During Thromboinflammation

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