Fig. 8

Proposed pathway by which increased IL-17 levels and activation of the IL-17 receptor in microglia induces neuroinflammation and activation of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway in cerebellum of hyperammonemic rats. IL-17 levels and membrane expression and activation of the IL-17 receptor are enhanced mainly in microglia of hyperammonemic rats, leading to increased activation of STAT3 and NF-κB, which increase the formation of IL-17 and TNFα, respectively. TNFα released by microglia activates its receptor TNFR1 in Purkinje neurons, leading to activation of the TNFα-TNFR1-S1PR2-CCL2 pathway in Purkinje neurons. CCL2 released from Purkinje neurons activates CCR2 in microglia, inducing microglia activation and increased content of BDNF. BDNF released from microglia activates TrkB-mediated signals in neurons, leading to increased membrane expression of KCC2. This would enhance GABAergic neurotransmission and induce motor incoordination. The effects of hyperammonemia are indicated by red arrows (↑). Blockade with anti-IL-17 antibody is shown in green