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Inflammation Leads to Distinct Populations of Extracellular Vesicles from Microglia Yiyi Yang1* , Antonio Boza-Serrano1, Christopher J

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Inflammation Leads to Distinct Populations of Extracellular Vesicles from Microglia Yiyi Yang1* , Antonio Boza-Serrano1, Christopher J Yang et al. Journal of Neuroinflammation (2018) 15:168 https://doi.org/10.1186/s12974-018-1204-7 RESEARCH Open Access Inflammation leads to distinct populations of extracellular vesicles from microglia Yiyi Yang1* , Antonio Boza-Serrano1, Christopher J. R. Dunning2, Bettina Hjelm Clausen3,4, Kate Lykke Lambertsen3,4,5 and Tomas Deierborg1* Abstract Background: Activated microglia play an essential role in inflammatory responses elicited in the central nervous system (CNS). Microglia-derived extracellular vesicles (EVs) are suggested to be involved in propagation of inflammatory signals and in the modulation of cell-to-cell communication. However, there is a lack of knowledge on the regulation of EVs and how this in turn facilitates the communication between cells in the brain. Here, we characterized microglial EVs under inflammatory conditions and investigated the effects of inflammation on the EV size, quantity, and protein content. Methods: We have utilized western blot, nanoparticle tracking analysis (NTA), and mass spectrometry to characterize EVs and examine the alterations of secreted EVs from a microglial cell line (BV2) following lipopolysaccharide (LPS) and tumor necrosis factor (TNF) inhibitor (etanercept) treatments, or either alone. The inflammatory responses were measured with multiplex cytokine ELISA and western blot. We also subjected TNF knockout mice to experimental stroke (permanent middle cerebral artery occlusion) and validated the effect of TNF inhibition on EV release. Results: Our analysis of EVs originating from activated BV2 microglia revealed a significant increase in the intravesicular levels of TNF and interleukin (IL)-6. We also observed that the number of EVs released was reduced both in vitro and in vivo when inflammation was inhibited via the TNF pathway. Finally, via mass spectrometry, we identified 49 unique proteins in EVs released from LPS-activated microglia compared to control EVs (58 proteins in EVs released from LPS- activated microglia and 37 from control EVs). According to Gene Ontology (GO) analysis, we found a large increase of proteins related to translation and transcription in EVs from LPS. Importantly, we showed a distinct profile of proteins found in EVs released from LPS treated cells compared to control. Conclusions: We demonstrate altered EV production in BV2 microglial cells and altered cytokine levels and protein composition carried by EVs in response to LPS challenge. Our findings provide new insights into the potential roles of EVs that could be related to the pathogenesis in neuroinflammatory diseases. Keywords: Microglia, Extracellular vesicles (EVs), Neuroinflammation, TNF Background [3]. Emerging evidence has shown that microglia are key Microglia are considered the main innate-immune cells of causative players in neuroinflammation, which in turn is the central nervous system (CNS). They continuously sur- believed to play a major role in neurodegenerative vey their microenvironment and have the ability to interact diseases [4]. with neurons to regulate their activity [1]. In the healthy Microglia are highly dynamic cells with the ability to brain, microglia continuously survey their surroundings transform their morphology from ramified to amoeboid with highly dynamic processes [2] and become activated in and alter their phenotypes corresponding to diverse con- response to injury, infection or neurodegenerative processes ditions. Traditionally, macrophages and microglial cells are classified into two different phenotypes, M1 and M2. M1-microglia are proinflammatory, secreting inflamma- * Correspondence: [email protected]; [email protected] 1Department of Experimental Medical Science, Experimental tory cytokines, chemokines, and nitric oxide (NO), Neuroinflammation Laboratory, Lund University, Lund, Sweden which is believed to result in neuronal dysfunction and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Journal of Neuroinflammation (2018) 15:168 Page 2 of 19 accelerate the progression of neurodegenerative diseases, changed after bacterial infection [17]. Thus, there is a such as Alzheimer’s disease (AD) and Parkinson’s disease critical need for both identification of specific markers (PD). In contrast, M2-microglia are believed to have and particular signaling pathways controlling EV traf- neuroprotective functions, including increased produc- ficking. The mechanism of action of EVs in microglial tion of interleukin (IL)-4 and neurotrophic factors, along communication is poorly understood. In this study, we with an increase in phagocytosis which in turn leads to hypothesized that activation of microglia can secrete a clearance of cell debris and tissue damage [3, 5]. How- distinct population of EV through modulation of specific ever, there is a wide spectrum of microglial activation signaling pathways. We investigated the dynamics of EVs between the two defined phenotypes [6], and microglia from activated microglial (BV2) cells subjected to lipo- might even have specific neuronal functions beyond typ- polysaccharide (LPS) stimulation. We used differential ical pro-/anti-inflammatory responses [7]. A better un- ultracentrifugation to isolate EVs, including microvesi- derstanding of the interactions between microglia and cles and exosomes. EVs were then characterized in terms other cells in the brain is therefore needed in order to of size and concentration by nanoparticle tracking design therapies to ameliorate the detrimental effects of analysis (NTA), while the origin of EVs was indicated by microglial reactions in brain diseases. western blotting using antibodies against CD63, flotillin-1, The main interaction between cells occur through cel- and Alix. Importantly, we also analyzed the levels of in- lular signaling pathways including autocrine, paracrine, flammatory cytokines in EVs. Secretion of EVs was altered and endocrine processes [8] and extracellular vesicles by suppression of inflammation in microglia via inhibition (EVs) can be important to transport signals between of tumor necrosis factor (TNF) signaling in vivo and in cells. In fact, increasing evidence has shown EVs are vitro. Subsequently, qualitative proteomic analysis was considered one of the main participants in cell-to-cell performed to reveal a different protein composition of communication along with having a proposed role in the EVs in response to LPS challenge. Taken together, our spread of pathology in neurodegenerative disease [9, 10]. findings provide new insights into the role of EVs in regu- These vesicles are able to carry pathogen-associated and lating microglial cell communication. damage-associated molecular patterns that act as signals to regulate and propagate the inflammatory response Methods [11–13]. Hence, investigation of EV trafficking under in- Cell culture flammatory conditions may broaden our understanding BV2, an immortalized murine microglial cell line, was of the roles of microglia in neurodegenerative diseases, cultured in growing medium containing Dulbecco’s as well as their potential in therapeutic manipulation. modified Eagle medium (DMEM) (Gibco™GlutaMAX™, The secretion of EVs is a highly conserved process Thermo Fisher Scientific) supplemented with 10% [14]. However, a number of studies using proteomic ana- heat-inactivated fetal bovine serum (FBS) and 1% peni- lysis of EVs released by various cell types, including cillin/streptomycin (Thermo Fisher Scientific) in 5% microglia, have revealed a diverse range of markers and CO2 in air at 37 °C in a humidified incubator. Cells were alteration of protein composition [15, 16]. The lack of re-cultured every 2 days starting at a concentration of knowledge on EV’s regulation in vitro and in vivo halts a 2×105 cells/ml in T75 flask (Sarstedt). For a large scale clear understanding of EV functions in cell-to-cell com- of EV collection, microglia were plated in T175 flask (Sar- munication. It is likely that different subsets of EVs have stedt). For inflammatory activation, cells were challenged different functional properties, and trafficking of EVs is with 1 μg/ml LPS (Sigma-Aldrich, Clony 0127-B8) for 12 h most likely modulated by specific signaling pathways. and then grown for 12 h in serum-free media prior to col- Although consensus within the field is being reached, lection of EVs. For TNF inhibition experiment, microglia the classification of EVs is not easy. While different sub- were plated in growing medium either with 1 μg/ml LPS, sets of EVs are being described with increasing rate, for 200 ng/ml etanercept, or both for 12 h. EVs were collected simplicity, we will focus on two different classes of EVs from serum-free media 12 h after treatment. of different sizes and origins. EVs shed directly from the plasma membrane are characterized as microvesicles or Animals ectosomes ranging from 100 to 1000 nm. Exosomes are Adult male C57BL/6 mice (between 7 and 8 weeks of
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