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Ager (Rage) and Myd88 deletion in resected mouse livers

ABSTRACT: The effect of resection of mouse livers on survival serve as a model for the effect of resection of human livers, which are performed for both the purposes of removing sick tissue and for transplanting healthy tissue. When less than 70% of a mouse liver is resected, the mouse usually lives. However, when more than 70% is resected, there is an increased probability that the mouse will die. We have found that deletion of Ager (Advanced Glycation End products receptor) (Rage) increases the chance of mouse survival relavtive to WT. Conversely, the deletion of Myd88 decreases the chances of survival, as does the simultaneous deletion of both Ager and Myd88. To understand these genotype/phenotype relations, we performed gene expression measurements.

ORGANISM(S): Mus musculus

PROVIDER: GSE22873 | GEO | 2012/06/26

SECONDARY ACCESSION(S): PRJNA128121

REPOSITORIES: GEO

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Project description:Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

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Ager (Rage) and Myd88 deletion in resected mouse livers

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