PERIPHERAL IL-17 TRIGGERS, AND ANTI-IL-17 TREATMENT PREVENTS, NEUROINFLAMMATION AND ALTERATIONS IN NEUROTRANSMISSION IN HIPPOCAMPUS AND COGNITIVE IMPAIRMENT IN HYPERAMMONEMIC RATS

In patients with liver cirrhosis minimal hepatic encephalopathy (MHE) appearance is associated with a shift in peripheral inflammation with increased IL-17. In animal models of hyperammonemia and MHE cognitive impairment is also triggered by peripheral inflammation, which induces neuroinflammation in hippocampus. How peripheral inflammation triggers neuroinflammation and cognitive impairment remains unclear. Rats with hyperammonemia and MHE show an early blood IL-17 increase. The aim was to assess if IL-17 induces cognitive impairment in hyperammonemic rats; identify the underlying mechanisms and assess if blocking peripheral IL-17 with anti-IL-17 prevents this process and cognitive impairment.
Hyperammonemic rats were injected with anti-IL-17 at days 2-4. The effects on blood-brain barrier (BBB), neuroinflammation and neurotransmission in hippocampus were analyzed by immunohistochemistry and Western blot. Cognitive impairment was assessed in object location, radial and Y maze tests.
In hyperammonemic rats peripheral IL-17 activates its receptor in endothelial cells leading to NADPH oxidase activation and superoxide formation. This increases MLCK, reduces occludin and ZO-1 and permeabilizes the BBB. This facilitates CD4 lymphocytes and monocytes infiltration and IL-17 entry. IL-17 activates microglia, increasing TNFα and TNFR1 membrane expression which increases IL-1β and membrane expression of IL-1 receptor and of the NR2B subunit of NMDA receptors. This alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors, leading to cognitive impairment.
Blocking peripheral IL-17 with anti-IL-17 at 2-4 days of hyperammonemia affords sustained prevention of cognitive impairment which remains four weeks after anti-IL-17 injection. Anti-IL-17 treatment could improve cognitive impairment in MHE patients.