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Extracellular Vesicles in Innate Immune Cell Programming

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Extracellular Vesicles in Innate Immune Cell Programming biomedicines Review Extracellular Vesicles in Innate Immune Cell Programming Naveed Akbar 1,* , Daan Paget 1,2 and Robin P. Choudhury 1 1 Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; [email protected] (D.P.); [email protected] (R.P.C.) 2 Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK * Correspondence: [email protected] Abstract: Extracellular vesicles (EV) are a heterogeneous group of bilipid-enclosed envelopes that carry proteins, metabolites, RNA, DNA and lipids from their parent cell of origin. They mediate cellular communication to other cells in local tissue microenvironments and across organ systems. EV size, number and their biologically active cargo are often altered in response to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic pertur- bations such as obesity and diabetes, which also have a strong inflammatory component. Here, we discuss the broad repertoire of EV produced by neutrophils, monocytes, macrophages, their pre- cursor hematopoietic stem cells and discuss their effects on the innate immune system. We seek to understand the immunomodulatory properties of EV in cellular programming, which impacts innate immune cell differentiation and function. We further explore the possibilities of using EV as immune targeting vectors, for the modulation of the innate immune response, e.g., for tissue preservation during sterile injury such as myocardial infarction or to promote tissue resolution of inflammation and potentially tissue regeneration and repair. Keywords: exosomes; transcription; neutrophil; monocyte; hematopoietic stem cell Citation: Akbar, N.; Paget, D.; Choudhury, R.P. Extracellular Vesicles in Innate Immune Cell Programming. Biomedicines 2021, 9, 713. https:// 1. Extracellular Vesicles doi.org/10.3390/biomedicines9070713 Extracellular vesicles (EV) are membrane-enclosed lipid envelopes that can medi- ate cellular communication locally in tissue microenvironments or upon liberation into Academic Editors: Andreas Spittler, peripheral blood [1–7], lymph [8] and cerebrospinal fluid [9] remotely from their site of Wolfgang Holnthoner and origin. EV bear features of their parent cells such as the presence of proteins, lipids and Viktoria Weber nucleic acids (mRNA, microRNAs (miRNAs), long non-coding RNAs and DNA), which are capable of initiating cellular signalling in recipient cells [10]. Importantly, EV from a Received: 13 May 2021 range of pathologies which have a strong inflammatory component such as infection, Accepted: 14 June 2021 Published: 23 June 2021 rheumatological diseases, cardiovascular diseases (including acute myocardial infarction, stroke and atherosclerosis), cancer and metabolic disorders such as obesity and diabetes Publisher’s Note: MDPI stays neutral show alterations in EV size, concentration, cargo and show effects on innate immune with regard to jurisdictional claims in cells [11–13]. Innate immune cells are the principal effector cells in the clearance of EV published maps and institutional affil- from the systemic circulation and they show predilection for EV uptake [14] compared iations. with other cells, such as lymphocytes [15,16]. Neutrophils and monocytes are present in peripheral blood and are recruited to sites of infection, injury and inflammation. Mechanisms of immune cell recruitment to tissues and the factors that enable their trafficking and infiltration are well documented [17,18]. Conventionally, innate immune cells patrol the systemic vasculature and undergo in- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. flammatory activation in response to local signalling, manifesting a broad repertoire of This article is an open access article pro-inflammatory and inflammation-resolving responses. In addition to the circulating distributed under the terms and pool, reserves of cells in the bone marrow and the spleen contribute large numbers of conditions of the Creative Commons immune cells to inflammation-related pathologies [19]. Acutely after sterile injury, such as Attribution (CC BY) license (https:// myocardial infarction, the spleen deploys large numbers of monocytes to the peripheral creativecommons.org/licenses/by/ blood, which mediate further injury to the heart [20]. Similarly, the spleen deploys neu- 4.0/). trophils following infection [21]. The functional characteristics of these peripheral blood Biomedicines 2021, 9, 713. https://doi.org/10.3390/biomedicines9070713 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 15 following infection [21]. The functional characteristics of these peripheral blood innate immune cells and those in the splenic and bone marrow reserve are becoming clearer though use of multi’-omics’ techniques. Single cell-RNA-sequencing (sc-RNA-seq) anal- Biomedicines 2021, 9, 713 2 of 15 yses have identified sub-sets of cells that perform important functions in myocardial in- jury [22–24] and tissue repair [25,26], potentially opening opportunities to modulate these cells therapeutically. innateWe immune have demonstrated cells and those a in role the for splenic endothelial and bone cell marrow derived reserve EV in areinnate becoming immune cell clearermobilisation though from use of the multi’-omics’ splenic reserve techniques. and in Single the cell-RNA-sequencingtranscriptional programming (sc-RNA-seq) of mono- analyses have identified sub-sets of cells that perform important functions in myocardial cytes and neutrophils in the blood, prior to recruitment to tissues [7,27]. Similar transcrip- injury [22–24] and tissue repair [25,26], potentially opening opportunities to modulate thesetional cells programming therapeutically. prior to tissue consignment is reported following viral infection e.g., SARsWe-CoV have-2, demonstrated brain aneurysms a role forand endothelial the peripheral cell derived monocyte EV in innatepool shows immune phenotypic cell mobilisationtrained immunity from the following splenic reserve inoculation and in the [28 transcriptional–30]. This demonstrates programming that of monocytes innate immune andcells neutrophils in a broad inrange the blood, of conditions prior to recruitmentshow transcriptional to tissues [7 alterations,27]. Similar prior transcriptional to tissue recruit- programmingment. Viral and prior inoculation to tissue consignment programming is reported and training following of innate viral infection immune e.g., cell SARs- may be me- CoV-2,diated brainin the aneurysms peripheral and blood the by peripheral viral components monocyte pool but showsthe manifestation phenotypic trainedof these tran- immunityscriptome following alterations inoculation in sterile [28 tissue–30]. Thisinjury demonstrates are poorly thatdescribed. innate immune EV are cellsa ubiquitous in ameans broad rangeof cell of communication, conditions show which transcriptional impact alterationsbroadly on prior innate to tissue immune recruitment. function [31]. ViralHere, and we inoculation focus on the programming opportunities and trainingfor immunomodulation of innate immune cellof neutrophils, may be mediated monocytes in the peripheral blood by viral components but the manifestation of these transcriptome and their pre-cursor haematopoietic stem and progenitor cells (HSCs) by EV (Figure 1). A alterations in sterile tissue injury are poorly described. EV are a ubiquitous means of cell communication,better understan whichding impact of how broadly immune on innate cells immune are transcriptionally function [31]. Here, activated we focus onand pro- thegrammed opportunities prior to for tissue immunomodulation recruitment by ofEV neutrophils, and during monocytes cellular differentiation and their pre-cursor could allow haematopoieticthe development stem of and targeted progenitor therapeutic cells (HSCs) strategies by EV (Figure, e.g., 1to). Apromote better understanding tissue resolution of ofpro how-inflamma immunetory cells signals are transcriptionally and induce tissue activated repair and and programmed regeneration.prior toTheretissue is recruit- considerable mentcrosstalk by EV between and during cancer cellular and tumour differentiation derived could EV, allowHSCs the and development their progeny of targetedbut these have therapeuticbeen recently strategies, reviewed e.g., and to promote will not tissue be discussed resolution in ofdetail pro-inflammatory here. [32] signals and induce tissue repair and regeneration. There is considerable crosstalk between cancer and tumour derived EV, HSCs and their progeny but these have been recently reviewed and will not be discussed in detail here [32]. FigureFigure 1. 1. TThehe crosstalkcrosstalk between between innate innate immune immune cells throughcells through the generation the generation and release and of extracellularrelease of extracellular vesicles. The knownvesicles. The known(solid lines)(solid and lines) proposed and proposed (dotted lines)(dotted role lines) of extracellular role of extracellular vesicles in vesicles the modulation in the modulation of neutrophils, of neutrophils, monocytes andmonocytes andmacrophages macrophages and theirand their pre-cursor pre-cursor hematopoietic hematopoietic stem cells stem (HSCs). cells (HSCs). Biomedicines 2021, 9, x FOR PEER REVIEW 3 of 15 Biomedicines 2021, 9, 713 3 of 15 2. Neutrophils Neutrophils are the most abundant leukocyte population in peripheral blood and 2. Neutrophilsarrive rapidly at sites of tissue inflammation, infection
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