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Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice
Matthew McMillin1,2, Stephanie Grant1,2, Gabriel Frampton1,2
1Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Fractalkine signaling is suppressed in acute liver failure leading to hepatic encephalopathy. Supplementing with fractalkine improved neurological outcomes and reduced liver damage, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Hepatology
- Immunology
Background:
- Acute liver failure causes hepatic encephalopathy, a neurological dysfunction linked to microglia activation and neuroinflammation.
- Fractalkine (CX3CL1) signaling via its receptor CX3CR1 normally suppresses microglia activation, but its role in hepatic encephalopathy is unknown.
- Neuroinflammation during hepatic encephalopathy involves dysregulated cell signaling and toxic metabolite accumulation in the brain.
Purpose of the Study:
- To investigate the expression and role of fractalkine in the pathogenesis of hepatic encephalopathy induced by acute liver failure.
- To determine if fractalkine supplementation can ameliorate neurological deficits and liver injury in a mouse model of hepatic encephalopathy.
Main Methods:
- Hepatic encephalopathy was induced in mice using azoxymethane (AOM); some received intracerebral fractalkine infusion.
- Neurological decline, coma latency, liver damage, and inflammatory markers were assessed.
- Gene and protein expression of fractalkine, CX3CR1, and cytokines were quantified using real-time PCR and ELISA.
Main Results:
- AOM administration suppressed neuronal fractalkine and microglial CX3CR1 expression.
- Intracerebral fractalkine infusion significantly reduced neurological decline and coma latency in AOM-treated mice.
- Fractalkine supplementation lessened liver damage, suppressed microglia activation, and decreased pro-inflammatory cytokine expression.
Conclusions:
- Fractalkine-mediated signaling is suppressed in the brain during hepatic encephalopathy.
- Restoring fractalkine signaling presents a potential therapeutic strategy for managing hepatic encephalopathy in acute liver injury.
