CD47 Signaling Induces Hepatic Cell Death and Microglia Activation During Hepatic Encephalopathy

Authors

• Ashwin Jhawer
• Gabriel Frampton
• Shadikchhya Maya Bhattarai
• Sharon DeMorrow
• Matthew McMillin

Language

English

Publication Date

12-10-2024

Journal

Metabolic Brain Disease

DOI

10.1007/s11011-024-01493-7

PMID

39656327

PMCID

PMC11705860

PubMedCentral® Posted Date

12-10-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, CD47 Antigen, Microglia, Mice, Mice, Inbred C57BL, Hepatic Encephalopathy, Signal Transduction, Mice, Knockout, Male, Liver, Cell Death, Azoxymethane, Liver Failure, Acute, CD47, acute liver failure, hepatic encephalopathy

Published Open-Access

yes

Recommended Citation

Jhawer, Ashwin; Frampton, Gabriel; Bhattarai, Shadikchhya Maya; et al., "CD47 Signaling Induces Hepatic Cell Death and Microglia Activation During Hepatic Encephalopathy" (2024). Faculty and Staff Publications. 8.
https://digitalcommons.library.tmc.edu/huffington_pub/8