FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia

Abstract

Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.