Peripheral IL-17 Triggers, and anti-IL-17 Treatment Prevents, Neuroinflammation and Alterations in Neurotransmission in Hippocampus and Cognitive Impairment in Hyperammonemic Rats.

Abstract

Patients with liver cirrhosis who develop minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with increased peripheral inflammation, including elevated interleukin-17 (IL-17). In animal models, this inflammation promotes neuroinflammation and disrupts glutamatergic neurotransmission in the hippocampus, contributing to cognitive deficits. This study investigated whether IL-17 is directly involved in cognitive impairment in hyperammonemic rats and explored the mechanisms involved. Hyperammonemic rats received intravenous anti-IL-17 treatment at days 3-5 after induction of hyperammonemia. Cognitive assessment and blood-brain barrier integrity, neuroinflammation, and glutamatergic neurotransmission in the hippocampus were performed after four weeks. Increased peripheral IL-17 activated its receptor in endothelial cells, enhancing NADPH oxidase activity and increasing Myosin light chain kinase (MLCK) levels. This reduced the tight junction proteins occludin and ZO-1, weakening the blood-brain barrier and facilitating immune cell infiltration and IL-17 entry into the hippocampus. Consequently, microglia became activated, increasing TNFα and IL-1β levels and altering membrane expression of glutamate receptors, leading to cognitive impairment. Blocking IL-17 prevented these pathological changes and produced sustained protection against cognitive deficits. These findings support a role of IL-17 in early transmission of peripheral inflammation into the brain initiating hippocampal neuroinflammation and cognitive impairment in MHE and propose anti-IL-17 therapies for MHE.