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Published on: January 30, 2014
CD47 signaling induces hepatic cell death and microglia activation during hepatic encephalopathy
Ashwin Jhawer1, Gabriel Frampton1, Shadikchhya Maya Bhattarai1
1Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Abstract:
Acute liver failure results from severe hepatic injury and can lead to neurological dysfunction known as hepatic encephalopathy (HE). Thrombospondin-1 can contribute to HE by increasing cerebral edema and microglia activation in the azoxymethane (AOM) mouse model. CD47 is a receptor for TSP1 and can directly modulate inflammation in numerous disease states. However, the role of CD47 in the progression of HE is currently unknown. Therefore, the aim of this study was to assess the role of CD47 in liver and brain pathology in the AOM mouse model of HE. C57Bl/6 or CD47 knockout (CD47-/-) were administered AOM to induce acute liver failure and HE. Liver damage was evaluated by measuring serum transaminases and histological assessment. Neurological function was determined by evaluating the time taken to reach coma (loss of all reflexes), cerebral edema, and microglia activation. CD47 signaling, and downstream signaling pathways, were assessed by real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. AOM-treated mice had increased expression of CD47 in the liver, cortex, hippocampus, and cerebellum when compared to vehicle-treated mice. CD47-/- AOM-treated mice had reduced liver injury and apoptosis when compared to wildtype AOM-treated mice. A slower degree of neurological decline and less cerebral edema were observed in CD47-/- mice compared to wildtype AOM-treated mice. This was associated with decreased microglia proliferation and increased SOD1 expression in CD47-/- mice compared to wildtype AOM-treated mice. These findings support that CD47 signaling exacerbates AOM-induced acute liver failure and HE by inducing hepatic cell death, cerebral edema, and microglia activation.
Insights
CD47 signaling worsens acute liver failure and hepatic encephalopathy (HE) by increasing liver injury, brain swelling, and inflammation. Blocking CD47 in mice reduced these effects, suggesting CD47 as a potential therapeutic target for HE.
Area of Science:
- Hepatology and Neuroscience
- Immunology and Molecular Biology
Background:
- Acute liver failure can cause hepatic encephalopathy (HE), a neurological disorder.
- Thrombospondin-1 (TSP1) exacerbates HE by increasing cerebral edema and microglia activation.
- CD47, a receptor for TSP1, modulates inflammation, but its role in HE is unknown.
Purpose of the Study:
- To investigate the role of CD47 in liver and brain pathology during azoxymethane (AOM)-induced acute liver failure and HE.
- To determine if CD47 signaling contributes to hepatic cell death, cerebral edema, and microglia activation in a mouse model.
Main Methods:
- Utilized azoxymethane (AOM) to induce acute liver failure and HE in wildtype and CD47 knockout (CD47-/-) mice.
- Assessed liver injury via serum transaminases and histology.
- Evaluated neurological function, cerebral edema, and microglia activation.
- Analyzed CD47 signaling pathways using molecular techniques (PCR, Western blotting, immunofluorescence, immunohistochemistry).
Main Results:
- AOM-treated mice showed increased CD47 expression in the liver and brain.
- CD47-/- mice exhibited reduced liver injury, apoptosis, cerebral edema, and neurological decline compared to wildtype.
- CD47 deficiency led to decreased microglia proliferation and increased SOD1 expression in the brain.
Conclusions:
- CD47 signaling significantly exacerbates AOM-induced acute liver failure and HE.
- CD47 blockade ameliorates liver damage, cerebral edema, and neuroinflammation.
- CD47 represents a potential therapeutic target for managing hepatic encephalopathy.
