Systemic Immune Response to Traumatic CNS Injuries-Are Extracellular Vesicles the Missing Link?

Abstract

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.

Keywords: acute phase response; extracellular vesicles; inflammation; spinal cord injury; traumatic brain injury.

Figure 1

EV biogenesis. EVs are typically classed according to their biogenesis. Apoptotic bodies and microvesicles are released from the plasma membrane in blebbing and budding mechanisms, respectively. In contrast, exosomes are generated by the endolysomal pathway; internal budding of an endosome results in a multivesicular body which fuses with the plasma membrane, releasing exosomes by exocytosis.

Figure 2

Visualized hypothesis of EV-mediated systemic inflammation response to traumatic CNS injury. Acute traumatic injuries to the brain and spinal cord induce the release of extracellular vesicles into circulation. These EVs localize to peripheral organs whereby they induce the production of pro-inflammatory molecules (chemokines, cytokines, acute phase proteins), in turn stimulating the mobilization of leukocytes which infiltrate both the CNS and peripheral organs. This systemic immune response is referred to as the acute phase response.