title: Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice.
abstract: Acute liver failure is associated with numerous systemic consequences including neurological dysfunction, termed hepatic encephalopathy, which contributes to mortality and is a challenge to manage in the clinic. During hepatic encephalopathy, microglia activation and neuroinflammation occur due to dysregulated cell signaling and an increase of toxic metabolites in the brain. Fractalkine is a chemokine that is expressed primarily in neurons and through signaling with its receptor CX3CR1 on microglia, leads to microglia remaining in a quiescent state. Fractalkine is often suppressed during neuropathies that are characterized by neuroinflammation. However, the expression and subsequent role of fractalkine on microglia activation and the pathogenesis of hepatic encephalopathy due to acute liver failure is unknown.
  
  
  
  Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) or saline for controls. Subsets of these mice were implanted with osmotic minipumps that infused soluble fractalkine or saline into the lateral ventricle of the brain. Neurological decline and the latency to coma were recorded in these mice, and brain, serum, and liver samples were collected. Neurons or microglia were isolated from whole brain samples using immunoprecipitation. Liver damage was assessed using hematoxylin and eosin staining and by measuring serum liver enzyme concentrations. Fractalkine and CX3CR1 expression were assessed by real-time PCR, and proinflammatory cytokine expression was assessed using ELISA assays.
  
  
  
  Following AOM administration, fractalkine expression is suppressed in the cortex and in isolated neurons compared to vehicle-treated mice. CX3CR1 is suppressed in isolated microglia from AOM-treated mice. Soluble fractalkine infusion into the brain significantly reduced neurological decline in AOM-treated mice compared to saline-infused AOM-treated mice. Infusion of soluble fractalkine into AOM-treated mice reduced liver damage, lessened microglia activation, and suppressed expression of chemokine ligand 2, interleukin-6, and tumor necrosis factor alpha compared to saline-infused mice.
  
  
  
  These findings suggest that fractalkine-mediated signaling is suppressed in the brain following the development of hepatic encephalopathy. Supplementation of AOM-treated mice with soluble fractalkine led to improved outcomes, which identifies this pathway as a possible therapeutic target for the management of hepatic encephalopathy following acute liver injury.
authors: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Central Texas Veterans Healthcare System, 1901 S. 1st Street, Building 205, Temple, TX, 76504, USA.
authors: Matthew
authors: M
authors: McMillin
authors: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Central Texas Veterans Healthcare System, 1901 S. 1st Street, Building 205, Temple, TX, 76504, USA.
authors: Stephanie
authors: S
authors: Grant
authors: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Central Texas Veterans Healthcare System, 1901 S. 1st Street, Building 205, Temple, TX, 76504, USA.
authors: Gabriel
authors: G
authors: Frampton
authors: Department of Internal Medicine, Baylor Scott & White Health, 2401 S. 31st Street, Temple, TX, 76508, USA.
authors: Sarah
authors: S
authors: Andry
authors: Department of Internal Medicine, Baylor Scott & White Health, 2401 S. 31st Street, Temple, TX, 76508, USA.
authors: Adam
authors: A
authors: Brown
authors: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA. demorrow@medicine.tamhsc.edu.|Central Texas Veterans Healthcare System, 1901 S. 1st Street, Building 205, Temple, TX, 76504, USA. demorrow@medicine.tamhsc.edu.
authors: Sharon
authors: S
authors: DeMorrow
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D001663:Bilirubin / Q000097:blood; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D005434:Flow Cytometry; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000150:complications*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D002273:Carcinogens; D054428:Chemokine CX3CL1; D016207:Cytokines; D008840:Microfilament Proteins; D000410:Alanine Transaminase; D010751:Phosphopyruvate Hydratase; D001397:Azoxymethane; D001663:Bilirubin
keywords: Acute liver failure; Azoxymethane; CCL2; CX3CL1; CX3CR1