Research reportBrain-derived microparticles activate microglia/macrophages and induce neuroinflammation
Introduction
With the development of modern society, road injuries have become the fifth leading cause of death following ischemic heart disease, lower respiratory infections, cerebrovascular disease and diarrheal diseases at 2013, from the rank ten at 1990 (GBD 2013 Mortality and Causes of Death Collaborators, 2015). In trauma patients, traumatic brain injury (TBI) and severe bleeding are the two main causes of death. The total proportion of these two could be as high as 80% or more (Sobrino and Shafi, 2013). Hence, TBI associated coagulopathy is one of the most serious case among TBI patients, which is resulted by a variety of mechanisms involved activated protein C, endothelial activation, platelet dysfunction and fibrinolysis (Chang et al., 2016). The incidence of TBI associated coagulopathy is reported from 10% to 97.2% in various studies (Zhang et al., 2012). The mortality rate of isolated TBI patients without coagulopathy was only 17.3%, and would increase to 50.4% when associated with coagulopathy (Wafaisade et al., 2010).
The mechanism of TBI associated coagulopathy has been a research hotspot for a long time. At present, studies have showed that TBI associated coagulopathy can be induced by many action ways, which can interconnect each other and make up a mechanism network (Chang et al., 2016). Microparticles (MPs) are cell vesicles secreted from apoptosis cells, which contain a kind of PS, and can participate in the extrinsic coagulation pathway. Our preliminary studies (Tian et al., 2015) first found that injured nerve and glial cells can release MPs, included brain derived MPs (BDMPs) and mitochondrial MPs (mtMP), which carried abundant tissue factor (TF) and phosphatidylserine (PS), causing widespread activation of exogenous coagulation cascade and hypercoagulable state after combined with the coagulation factor VIIa and Ca2+. When the excessive consumption of coagulation factors, the hypercoagulable state transformed to hypocoagulable state, producing consumptive coagulopathy.
Although our previous study have showed apoptotic cell-scavenging factor lactadherin, which well-known secreted by microglia/macrophages, can prevent coagulopathy by enhancing the clearance of BDMPs through phosphatidylserine-mediated phagocytosis (Zhou et al., 2017), the interaction between BDMPs and microglia/macrophages have not been studied. Here, we report that BDMPs can combine by microglia/macrophages and upregulate the production of pro-inflammatory factors in mice either in vitro or in vivo.
Section snippets
BDMPs binding to microglia/macrophages
We obtained the results that BDMPs could binding to the microglia/macrophages by confocal microscopy. We pre-stained the BDMPs with the membrane fluorescent dye PKH26 (red), then co-cultured with microglia/macrophage BV2 cells. We observed some red spots on the surface of BV2 cells, which stained by phalloidin (green) to mark the cytoskeleton (Fig. 1). The results indicated BDMP could binding to microglia/macrophages.
BDMPs activate microglia/macrophages
After BDMPs were binding to microglia/macrophages, we observed the morphology
Discussion
Our previous study showed that injured brain cells could release BDMPs into peripheral blood, which had rich of tissue factor and phosphatidylserine on the surface of BDMPs, leading to transform from hypercoagulable state to consumable hypocoagulable state after traumatic brain injury (Wafaisade et al., 2010). In this study, we made several novel observations that how BDMPs reaction with microglia/macrophages after release into surrounding brain tissues.
First, we demonstrated that BDMPs can be
Animals
The studies were performed using adult male C57BL/6 mice (20–25 g). The mice were housed in the animal facilities of Tianjin Medical University General Hospital under a 12 h light/dark cycle with ad libitum access to food and water. All surgical procedures were performed in accordance with protocols approved by the Chinese Small Animal Protection Association.
Preparation of BDMPs
The mice were anesthetized with 10% chloral hydrate via an intraperitoneal injection (3 mg/kg). After sacrifice, the brain tissues were
Funding
This work was supported by the National Natural Science Foundation of China (Grant No.: 81501057 and 81671380), Tianjin Natural Science Foundation (Grant No.: 16JCQNJC10600, 17JCQNJC12000, 15JCQNJC11300 and 17JCZDJC35900), Tianjin Research Program of Application Foundation and Advanced Technology (Grant No.: 15JCQNJC11300) the Tianjin Medical University General Hospital Funding (Grant No.: ZYYFY201614 and ZYYFY201616) and The Sience & Technology Development Fund of Tianjin Education Commission
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These authors have contributed equally to this work.