Elevated circulating TGF?1 during acute liver failure activates TGF?R2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice.

ABSTRACT: BACKGROUND:Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGF?1) is upregulated due to liver failure in mice and inhibiting circulating TGF? reduced HE progression. However, the specific contributions of TGF?1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGF?1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. METHODS:C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGF?R2) null mice (TGF?R2?Neu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGF?1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGF?1 (anti-TGF?1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGF?1 signaling in HT-22 and EOC-20 cells. RESULTS:TGF?1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGF?1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGF?R2?Neu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGF?1 or in TGF?R2?Neu mice. TGF?1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNF?) expression, and phagocytosis activity in EOC-20 cells. CONCLUSION:Increased circulating TGF?1 following acute liver failure results in activation of neuronal TGF?R2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.

SUBMITTER: McMillin M 

PROVIDER: S-EPMC6446280 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature