Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk

Author:

Freel Bethany A.12,Kelvington Benjamin A.2,Sengupta Sonali2,Mukherjee Malini3,Francis Kevin R.24ORCID

Affiliation:

1. Basic Biomedical Sciences, University of South Dakota 1 , Vermillion, SD 57069 , USA

2. Cellular Therapies and Stem Cell Biology Group, Sanford Research 2 , Sioux Falls, SD 57104 , USA

3. Functional Genomics and Bioinformatics Core, Sanford Research 3 , Sioux Falls, SD 57104 , USA

4. Sanford School of Medicine, University of South Dakota 4 Department of Pediatrics , , Sioux Falls, SD 57105 , USA

Abstract

ABSTRACT Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith–Lemli–Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte–microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte–microglia immune axis, with possible implications in other neurological diseases.

Funder

National Institutes of Health

National Institute of General Medical Sciences

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Science Foundation

Smith-Lemli-Opitz/RSH Foundation

Sanford Research

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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