Proinflammatory Extracellular Vesicle-Mediated Signaling Contributes to the Induction of Neuroinflammation in Animal Models of Endotoxemia and Peripheral Surgical Stress

Abstract

Peripheral inflammation induced by endotoxemia or surgical stress induces neuroinflammation thereby causing neurological symptoms ranging from sickness behavior to delirium. Thus, proinflammatory signaling must be operative between the periphery and the central nervous system (CNS). In the present study, we tested whether nanometer-sized extracellular vesicles (EVs) that were produced during the peripheral inflammatory process have the capacity to induce neuroinflammation. Conditions of endotoxemia or surgical intervention were simulated in rats by lipopolysaccharide (LPS) injection or partial hepatectomy (HpX). EVs were concentrated from these animals and tested for their proinflammatory action (I) in a microglial cell line and (II) by intracerebroventricular and (III) by intravenous injections into healthy rats. EVs from both conditions induced the secretion of cytokines from the glial cell line. Intracerebroventricular injection of the EVs caused the release of inflammatory cytokines to the cerebrospinal fluid indicating their pro-neuroinflammatory capacity. Finally, proinflammatory EVs were shown to pass the blood–brain barrier and induce neuroinflammation after their intravenous injection. Based on these data, we suggest that EV-associated proinflammatory signaling contributes to the induction of neuroinflammation in endotoxemia and peripheral surgical stress. Preliminary results suggest that peripheral cholinergic signals might be involved in the control of proinflammatory EV-mediated signaling from the periphery to the brain.

Extracellular Vesicles as a Means of Viral Immune Evasion, CNS Invasion, and Glia-Induced Neurodegeneration

“…In a separate study, it was shown that EVs isolated from the serum of lipopolysaccharide-treated or high-fat diet mice were able to activate microglia and astrocytes when injected peripherally in healthy mice, suggesting that these EVs not only cross the BBB but also impact resident cells (Li et al, 2018 ). Similarly, EVs isolated from the serum of two different models of peripheral inflammation were able to cross the BBB and induce neuroinflammation when injected intravenously into healthy rats (Fricke et al, 2020 ). Balusu et al ( 2016 ) found that peripheral inflammation also increased the number of EVs released from choroid-plexus epithelium cells into the cerebrospinal fluid which were able to pass ependymal cells and be taken up by astrocytes and microglia causing an inflammatory response in the brain.…”

“…Neuroinflammation and neurotoxicity have been associated with EVs in a variety of settings. EVs isolated from the serum of rats exposed to lipopolysaccharide or a partial hepatectomy were capable of inducing the release of proinflammatory cytokines in cerebrospinal fluid, both when administered intracerebroventricularly or peripherally to naïve rats (Fricke et al, 2020 ). This suggests EVs in the blood not only cross the BBB but also induce neuroinflammation once within the brain.…”

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans

“…Here, we explored the idea that besides cytokines, also circulating EVs from the periphery may affect neuronal health and transmission, an issue only partially addressed for hematopoietic EVs [ 42 , 65 ]. Interestingly, modifications induced by EVs treatment have been described already, to occur after a short temporal window (within hours) both in vitro and in vivo [ 40 , 41 , 66 , 67 ]. Thus, we decided to evaluate the effects mediated by a two hours incubation with EVs extracted from synovial fluid of RA and OA patients on mature hippocampal neurons (14-day-old, DIV 14) derived from wt mouse embryos.…”

“…On the contrary, the direct impact of EVs coming from the inflamed peripheries to neurons is much less investigated. Indeed, only recently it has been shown that (i) pro-inflammatory EVs from the periphery have the potential to induce inflammation in the brain as revealed by ELISA quantification of TNF and IL-1B levels, and (ii) the ability of peripheral EVs to pass the BBB [ 41 , 42 , 43 ].…”

Neuroinflammation of traumatic brain injury: Roles of extracellular vesicles

“…LPS-stimulated serum-derived EVs promote the activation of microglia and astrocytes and mRNA expression of pro-inflammatory factors and miR-155 ( 154 ). Intracerebroventricular injection of pro-inflammatory EVs causes the release of pro-inflammatory cytokines in the CSF, and these EVs intravenously injected have the ability to cross the BBB and induce neuroinflammation ( 155 ). EVs from the plasma of hyperammonemic rats show altered protein cargo, which is primarily related to immune system processes.…”