Disclosures: The following people have nothing to disclose: Bharat Bhushan, Chad M. Wale-sky, Prachi C. Borude, Genea Edwards, Michael Manley, Satdarshan
(Paul) S. Monga, Udayan Apte Neuroinflammation is an integral component of hepatic encephalopathy (HE). The chemokine monocyte chemoattractant protein 1 (MCP-1) regulates microglia activation via binding the chemokine receptors 2 (CCR2) and 4 (CCR4). We have previously shown that CCL2 is involved in the pathogenesis of HE due to both acute and chronic liver injury. Conversely, the chemokine fractalkine (FKN) is highly expressed in the brain and serves as a suppressor of microglia activation. Bile acids regulate a number of inflammatory processes in the liver. We have shown that bile acids access the brain and contribute to the progression of HE, though little is known about bile acid signaling VX-809 chemical structure in the regulation of neuroinflammation. Therefore, Alvelestat we tested the hypothesis that serum bile acids alter the balance between MCP-1 and FKN expression, thereby supporting a pro-inflammatory environment in a murine
model of HE. Methods: HE was induced by injecting male C57Bl/6 mice with azoxymethane (AOM) (100 μg/g ip) in the presence of CCR2 and CCR4 antagonists, or after feeding a diet enriched in the bile acid sequestrant, cholestyramine, for 3 days. Neurological decline was assessed by measuring reflex impairment, degree of ataxia and time taken to reach to coma. Microglia activation was assessed by morphometric analysis of Iba-1 immunoreactivity. Primary cortical neuronal cultures were treated in vitro with the bile acids cholic acid (CA) and taurocholic acid (TCA) for 24 hr. MCP-1 and FKN expression was assessed in the frontal cortex as well as neuronal cultures by qPCR and immunofluorescence. Results: MCP-1 was upregulated and FKN was downregulated in frontal cortex neurons rapidly following AOM injection. Pretreatment of AOM-injected
mice with CCR2 and CCR4 antagonists delayed neurological decline and microglia activation, implicating MCP-1 signaling in HE. Treatment of primary neurons with CA and TCA increased MCP-1 expression and decreased FKN expression. Cholestyramine feeding reduced MCE serum and brain bile acid levels and delayed neurological decline without altering liver damage observed after AOM injection. Furthermore, cholestyramine prevented the AOM-induced increase in MCP-1 and decrease in FKN and suppressed microglia activation. Conclusions: Our data demonstrate that bile acids facilitate an imbalance between MCP-1 and FKN, which leads to a proinflammatory environment. Targeting bile acid, FKN or MCP-1 signaling may prove to be viable options for the management of HE during liver injury. Disclosures: The following people have nothing to disclose: Matthew McMillin, Gabriel A. Frampton, Cheryl Galindo, Holly A.