Fig. 5.

Mechanisms and consequences of microglial activation in hepatic encephalopathy.

In (chronic) liver disease, circulating levels of ammonia, TCA, TGFβ1 and cytokines like TNF are increased. TGFβ1, TNF and TCA bind to their respective neuronal receptors, which respond with CCL2 production. CCL2 binds to CCR2/4 on microglia, resulting in an activated phenotype. Additionally, hyperammonaemia can induce peripheral TNF increases, which induces microglial activation through the TNFR1, although whether this effect is direct or indirect is not known. Whether compounds like bile acids and cytokines have a direct influence on microglia in HE is unknown. The direct effect of hyperammonaemia on microglia is still an open question. Microglial activation results in cytokine production and recruitment of peripheral immune cells, in particular monocytes. This constitutes a neuroinflammatory environment, which is detrimental to brain functioning. CCL, chemokine ligand; CCR, C-C chemokine receptor; NH₃, ammonia; TCA, taurocholic acid; TGFβ, transforming growth factor beta; TNF, tumour necrosis factor; TNFR1, TNF receptor 1.