Exacerbation of Acute Traumatic Brain Injury by Circulating Extracellular Vesicles

Abstract

Inflammatory lesions in the brain activate a systemic acute-phase response (APR), which is dependent on the release of extracellular vesicles (EVs) into the circulation. The resulting APR is responsible for regulating leukocyte mobilization and subsequent recruitment to the brain. Factors that either exacerbate or inhibit the APR will also exacerbate or inhibit central nervous system (CNS) inflammation as a consequence and have the potential to influence ongoing secondary damage. Here, we were interested to discover how the circulating EV population changes after traumatic brain injury (TBI) and how manipulation of the circulating EV pool impacts on the outcome of TBI. We found the number of circulating EVs increased rapidly post-TBI, and this was accompanied by an increase in CNS and hepatic leukocyte recruitment. In an adoptive transfer study, we then evaluated the outcomes of TBI after administering EVs derived from either in vitro macrophage or endothelial cell lines stimulated with lipopolysaccharide (LPS), or from murine plasma from an LPS challenge using the air-pouch model. By manipulating the circulating EV population, we were able to demonstrate that each population of transferred EVs increased the APR. However, the characteristics of the response were dependent on the nature of the EVs; specifically, it was significantly increased when animals were challenged with macrophage-derived EVs, suggesting that the cellular origins of EVs may determine their function. Selectively targeting EVs from macrophage/monocyte populations is likely to be of value in reducing the impact of the systemic inflammatory response on the outcome of traumatic CNS injury.

Extracellular Vesicles: Packages Sent With Complement

“…Noteworthy, EVs also play critical roles in TBI ( 132 ). Similar to other injuries, cell–cell communication is critical for regulating the immune response in TBI ( 133 ).…”

Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers

“…In fact, Kurachi et al showed that EVs derived from various ECs (aortic, brain, umbilical) have similar effects on oligodendrocytes [ 63 ], which suggests potential similarities among EVs from different vascular beds in executing some actions. Although cross-talk between the vascular lineages has not been examined, it has been demonstrated by adoptive transfer of BMEC-derived EVs (in vivo) that these vesicles can have an effect on other organ systems such as the liver [ 64 , 65 ].…”

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

“…The latter include activation of inflammatory cytokines, chemokines, and micro-RNAs (miRs) (Perry et al, 2010;Prinz and Priller, 2014). Activated microglia also release extracellular vesicles (EVs), including microparticles (MP; also called microvesicles) and exosomes containing pro-inflammatory molecules, which can further enhance and potentially propagate the inflammatory response after TBI (Hazelton et al, 2018;Paolicelli et al, 2018). Several in vitro and in vivo models, including lipopolysaccharide (LPS)-treated primary microglia, cell lines (e.g., BV2 microglia), and LPS-challenged mice have been used to mimic such neurotoxic microglial activation (Loane et al, 2009;Mao et al, 2012;Fenn et al, 2014;Yuan et al, 2015;Hung et al, 2017).…”