Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury

Abstract

BackgroundLocal and systemic inflammatory responses are initiated early after traumatic brain injury (TBI), and may play a key role in the secondary injury processes resulting in neuronal loss and neurological deficits. However, the mechanisms responsible for the rapid expansion of neuroinflammation and its long-term progression have yet to be elucidated. Here, we investigate the role of microparticles (MP), a member of the extracellular vesicle family, in the exchange of pro-inflammatory molecules between brain immune cells, as well as their transfer to the systemic circulation, as key pathways of inflammation propagation following brain trauma.MethodsAdult male C57BL/6 mice were subjected to controlled cortical impact TBI for 24 h, and enriched MP were isolated in the blood, while neuroinflammation was assessed in the TBI cortex. MP were characterized by flow cytometry, and MP content was assayed using gene and protein markers for pro-inflammatory mediators. Enriched MP co-cultured with BV2 or primary microglial cells were used for immune propagation assays. Enriched MP from BV2 microglia or CD11b-positive microglia from the TBI brain were stereotactically injected into the cortex of uninjured mice to evaluate MP-related seeding of neuroinflammation in vivo.ResultsAs the neuroinflammatory response is developing in the brain after TBI, microglial-derived MP are released into the circulation. Circulating enriched MP from the TBI animals can activate microglia in vitro. Lipopolysaccharide stimulation increases MP release from microglia in vitro and enhances their content of pro-inflammatory mediators, interleukin-1β and microRNA-155. Enriched MP from activated microglia in vitro or CD11b-isolated microglia/macrophage from the TBI brain ex vivo are sufficient to initiate neuroinflammation following their injection into the cortex of naïve (uninjured) animals.ConclusionsThese data provide further insights into the mechanisms underlying the development and dissemination of neuroinflammation after TBI. MP loaded with pro-inflammatory molecules initially released by microglia following trauma can activate additional microglia that may contribute to progressive neuroinflammatory response in the injured brain, as well as stimulate systemic immune responses. Due to their ability to independently initiate inflammatory responses, MP derived from activated microglia may provide a potential therapeutic target for other neurological disorders in which neuroinflammation may be a contributing factor.

Innate immune responses to trauma

“…Pro-coagulatory molecules and microparticles loaded with TF and phosphatidylserine derived from microglia and astrocytes can activate platelets and induce a hypercoagulatory state or even a consumptive coagulopathy 126,127 . Similarly, pro-inflammatory molecules in microglia-derived microparticles can add to the inflammatory response 128 .…”

Fibroblast Growth Factor 2‐Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

“…The presence of EVs in cerebrospinal fluid (CSF) underscores their relevance in neural tissue . In the injured CNS, EVs were recently found to cross the blood–brain barrier and promote neuroinflammation . Furthermore, certain types of EVs appear to support neuronal survival under conditions of ischemic stress .…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…Microglial activation within the injured area is observed within 6-48 hours post injury [99] but evidence has shown that microglia can maintain a primed or pro-inflammatory profile for weeks to months after the acute effects of injury have dissipated [106]. Recently, it was shown that extracellular vesicles may exchange pro-inflammatory molecules between brain immune cells, as well as to the systemic circulation, as pathways of inflammation propagation following TBI [107].…”

“…Previous studies indicated that MSCs promised to be an effective therapy for brain injury in TBI [175-177, 215, 231-236]. Instead of brain remodeling and functional recovery by cell replacement effects, evidence suggests that the major effects of neurorestoration were due to the paracrine effects of secretion-based factors such as MSCs-derived exosomes that may reduce neuroinflammation, promote neurogenesis and angiogenesis, rescue pattern separation and spatial learning impairments, and improve functional recovery after TBI in animal models [107,176,178,191,204,205,215,216,[235][236][237]. In addition, as exosomes contain various miRNAs, which play a key role in modifying the phenotype and/or the physiology and modulating the cellular processes of the recipient cell, and miRNAs such as miR-21 could be potential therapeutic targets for interventions after TBI, the combination of miRNAs and MSC-derived exosomes might be a novel approach for the treatment of TBI [238].…”

“…Regarding the brain, impacts of MSC-EV treatment were mainly studied in models for ischemic stroke and TBI and reduced apoptosis rates in affected brains, while promoted angiogenesis and neurogenesis [175-177, 215, 231-236]. Both systemic pro-inflammatory and neuroinflammatory cues were reduced following MSC-EV treatment [107,215].…”