25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Abstract

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and in response to different inflammatory stimuli overexpress a proinflammatory signature of genes. Among these,Ch25his a gene overexpressed in brain tissue from Alzheimer’s disease as well as various mouse models of neuroinflammation.Ch25hencodes cholesterol 25-hydroxylase, an enzyme that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC, an immune-oxysterol primarily produced by activated microglia, is further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant for leukocytes. We have also previously shown that 25HC increases production and secretion of the proinflammatory cytokine, IL-1β, by mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) andCh25h-knockout (CKO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treatedWTmice,Ch25hexpression and 25HC levels increased in brain relative to vehicle-treatedWTmice. Interestingly, 25HC levels were significantly higher in LPS-treatedWTfemale compared to male mice. Activation of microglia and astrocytes in response to systemic LPS was suppressed inCKOmice relative toWTmice. Proinflammatory cytokine production and intra-parenchymal infiltration of neutrophils strongly correlated with brain 25HC levels and were significantly lower inCKOcompared toWTmice. Overall, our results show that 25HC mediates a sex-specific proinflammatory response in the brain characterized by activation of both microglia and astrocytes but also by neutrophil migration into the brain parenchyma presumably due to 7α,25-diHC produced from 25HC.