Extracellular Vesicles from Peripheral Blood Mononuclear Cells of Hyperammonemic Rats Induce Neuroinflammation in...

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment. Studies in patients and animal models show that MHE is triggered by a shift in peripheral inflammation. Peripheral extracellular vesicles (EVs) seem to mediate transmission of deleterious effects to the brain. However, it is not known which cell types produce the pathological EVs. The aim of this study was to assess if EVs released from cultured peripheral blood mononuclear cells from hyperammonemic rats with MHE (HA-PBMC-EVs) transmit pathological signals to the brain when injected into normal rats and to analyze the underlying mechanisms. We found that HA-PBMC-EVs induce neuroinflammation in hippocampus and cognitive impairment in normal rats, indicating that hyperammonemia alters the EVs released by PBMCs, which mediate cognitive impairment induction. We also identified underlying mechanisms: HA-PBMC-EVs enhance membrane expression and activation of TNFR1 and of S1PR2, increasing IL-1β and phosphorylation of Src, which increases CCL2 and BDNF content and membrane expression of the GLUN2B subunit of the NMDA receptor. BDNF activates TrkB, leading to phosphorylation and activation of Akt, which further increases BDNF. The increased activation of GLUN2B alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors, which would be responsible for the induction of cognitive impairment. Moreover, blocking TNFα in the HA-PBMC-EVs prevents the activation of the TNFα-TNFR1-S1PR2-IL-1β-Src-BDNF-TrkB pathway and the changes in membrane expression of NMDA and AMPA receptors. EVs from PBMC may be therefore a therapeutic target on which to act to reverse cognitive impairment in patients with MHE.