SEMINAR: María Ángeles Pedrosa Sánchez

Speaker: María Ángeles Pedrosa Sánchez

Title: Extracellular vesicles from peripheral immune cells of hyperammonemic rats induce neuroinflammation and cognitive impairment. Underlying mechanisms.

Abstract: Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation and characterized by cognitive and motor impairments. Our group has shown that liver disease induces both in patients and in animal models peripheral inflammation and immune alterations that are transmitted to the brain, leading to neuroinflammation and alteration of neurotransmission. Blocking peripheral TNF-α reverses brain pathology in experimental models, highlighting the key role of TNF-α–mediated peripheral-to-brain communication in the induction of MHE. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types, including CD4+ T lymphocytes and monocytes. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFa and PKA in these mechanisms.
In hyperammonemic rats, monocytes but not CD4+ lymphocytes release pathological EV. Hyperammonemia increases the EV release by monocytes and their content of TNFR1 and TNFa. These EV induce activation of glia and of the TNFa–TNFR1–S1PR2−IL-1b–CCL2–BDNF–TrkB pathway and alterations in membrane expression of NMDA and AMPA receptors in hippocampal slices from control rats. Concerning the mechanisms by which hyperammonemia induces these effects in monocytes, we found that it increases TNFa levels, which increases cAMP and PKA activity and reduces LC3 content. This leads to autophagy–lysosome dysfunction, with altered LC3, cathepsin L, and LAMP2 content and pH that increases the release of EV and their TNFR1 and TNFa content. All these changes are reversed by blocking TNFa with anti-TNFa or inhibiting PKA with an inhibitor.
These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE.