Contribution of extracellular vesicles to neuroinflammation and cognitive and motor deficits in hyperammonemia and hepatic encephalopathy

Abstract

Cirrhotic patients can present hepatic encephalopathy (HE), showing motor and cognitive deficits. Hyperammonemia and peripheral inflammation are known to induce neuroinflammation and alter neurotransmission, which finally induces neurological impairment in HE. However, the mechanisms by which the deleterious effects of peripheral inflammation are transmitted to the brain are not well understood. Extracellular vesicles (EVs) have recently emerged as a new mediator between the periphery and the brain, particularly in pathologies associated with sustained inflammation and in neurological disorders. In this work, we summarized the main findings on the role of plasma EVs in hyperammonemia and HE and discussed its potential implication in the pathogenesis of hepatic encephalopathy.

Keywords

Hepatic encephalopathy / extracellular vesicles / motor incoordination / memory impairments / hippocampus / cerebellum / TNFα

References

[1] Felipo V.Hepatic encephalopathy: effects of liver failure on brain function.Nat Rev Neurosci2013;14:851-8

[2] Häussinger D,Felipo V.Hepatic encephalopathy.Nat Rev Dis Primers2022;8:43

[3] Weissenborn K.Hepatic encephalopathy: definition, clinical grading and diagnostic principles.Drugs2019;79:5-9 PMCID:PMC6416238

[4] Shawcross DL,Olde Damink SW.Role of ammonia and inflammation in minimal hepatic encephalopathy.Metab Brain Dis2007;22:125-38

[5] Felipo V,Montesinos E.Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy.Metab Brain Dis2012;27:51-8

[6] Balzano T,Arenas YM,Felipo V.Hepatic encephalopathy: investigational drugs in preclinical and early phase development.Expert Opin Investig Drugs2023;32:1055-69

[7] Cabrera-Pastor A,Montoliu C.Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications.Acta Physiol2019;226:e13270

[8] Nguyen K,Le T,Swain MG.Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice.J Hepatol2012;56:626-31

[9] D'Mello C,Swain MG.Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation.J Neurosci2009;29:2089-102 PMCID:PMC6666330

[10] Balzano T,Ivaylova G.Rifaximin prevents T-lymphocytes and macrophages infiltration in cerebellum and restores motor incoordination in rats with mild liver damage.Biomedicines2021;9:1002 PMCID:PMC8393984

[11] Izquierdo-Altarejos P,Gonzalez-King H,Felipo V.Extracellular vesicles from hyperammonemic rats induce neuroinflammation and motor incoordination in control rats.Cells2020;9:572 PMCID:PMC7140428

[12] Izquierdo-Altarejos P,Felipo V.Extracellular vesicles from hyperammonemic rats induce neuroinflammation in cerebellum of normal rats: role of increased TNFα content.Front Immunol2022;13:921947 PMCID:PMC9325972

[13] Izquierdo-Altarejos P,Felipo V.Extracellular vesicles from hyperammonemic rats induce neuroinflammation in hippocampus and impair cognition in control rats.Cell Mol Life Sci2023;80:90

[14] Ridder K,Dams M.Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation.PLoS Biol2014;12:e1001874 PMCID:PMC4043485

[15] Li JJ,Kodali MC.In vivo evidence for the contribution of peripheral circulating inflammatory exosomes to neuroinflammation.J Neuroinflammation2018;15:8 PMCID:PMC5759808

[16] Matsumoto J,Sheng L.Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease?.Acta Neuropathol Commun2017;5:71 PMCID:PMC5598000

[17] Han C,Guo X.Exosomes from patients with Parkinson's disease are pathological in mice.J Mol Med2019;97:1329-44

[18] Sardar Sinha M,Civitelli L.Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers.Acta Neuropathol2018;136:41-56 PMCID:PMC6015111

[19] Elsherbini A,Zhu Z,Crivelli SM.In vivo evidence of exosome-mediated Aβ neurotoxicity.Acta Neuropathol Commun2020;8:100 PMCID:PMC7339450

[20] Fiandaca MS,Mapstone M.Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study.Alzheimers Dement2015;11:600-7.e1 PMCID:PMC4329112

[21] Wang Y,Kaniyappan S.The release and trans-synaptic transmission of Tau via exosomes.Mol Neurodegener2017;12:5 PMCID:PMC5237256

[22] Cabrera-Pastor A,Hernández-Rabaza V,Llansola M.Increasing extracellular cGMP in cerebellum in vivo reduces neuroinflammation, GABAergic tone and motor in-coordination in hyperammonemic rats.Brain Behav Immun2018;69:386-98

[23] Arenas YM,Ivaylova G,Felipo V.The S1PR2-CCL2-BDNF-TrkB pathway mediates neuroinflammation and motor incoordination in hyperammonaemia.Neuropathol Appl Neurobiol2022;48:e12799

[24] Taoro-Gonzalez L,Cabrera-Pastor A.Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus by enhancing activation of the IL-1 receptor: underlying mechanisms.J Neuroinflammation2018;15:36 PMCID:PMC5806265

[25] Momen-Heravi F,Kodys K,Satishchandran A.Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis.J Transl Med2015;13:261 PMCID:PMC4533956

[26] Manakeng K,Phongpao K.Elevated levels of platelet- and red cell-derived extracellular vesicles in transfusion-dependent β-thalassemia/HbE patients with pulmonary arterial hypertension.Ann Hematol2019;98:281-8

[27] Pardo F,Sobrevia B,Sobrevia L.Extracellular vesicles in obesity and diabetes mellitus.Mol Aspects Med2018;60:81-91

[28] Tan DBA,Teo TH,Shin H.Elevated levels of circulating exosome in COPD patients are associated with systemic inflammation.Respir Med2017;132:261-4

[29] Tsilioni I.Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1β.J Neuroinflammation2018;15:239 PMCID:PMC6112123

[30] Zhang HG,Su K.A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death.J Immunol2006;176:7385-93

[31] Obregon C,Gerber P,Nicod LP.Active uptake of dendritic cell-derived exovesicles by epithelial cells induces the release of inflammatory mediators through a TNF-alpha-mediated pathway.Am J Pathol2009;175:696-705 PMCID:PMC2715287

[32] Gao W,Yuan J.Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway.J Cell Mol Med2016;20:2318-27 PMCID:PMC5134386

[33] Perdriger A.Infliximab in the treatment of rheumatoid arthritis.Biologics2009;3:183-91 PMCID:PMC2726073

[34] Sandborn WJ.Infliximab in the treatment of Crohn's disease: a user's guide for clinicians.Am J Gastroenterol2002;97:2962-72

[35] Balzano T,Forteza J.Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: Reversed by anti-TNF-α treatment.J Hepatol2020;73:582-92

[36] Gallego JJ,Casanova-Ferrer F.Plasma extracellular vesicles play a role in immune system modulation in minimal hepatic encephalopathy.Int J Mol Sci2022;23:12335 PMCID:PMC9604313

[37] Mangas-Losada A,Urios A.Minimal hepatic encephalopathy is associated with expansion and activation of CD⁴⁺CD28^-, Th22 and Tfh and B lymphocytes.Sci Rep2017;7:6683 PMCID:PMC5532287