25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner

• DOI: 10.1186/s12974-020-01869-3
• Publication Date: 2020-06-17T07:02:48Z
• Authors: Man Ying Wong; Michael Lewis; James J. Doherty; Yang Shi; Anil G. Cashikar; Anna Amelianchik; Svitlana Tymchuk; Patrick M. Sullivan; Mingxing Qian; Douglas F. Covey; Gregory A. Petsko; David M. Holtzman; Steven M. Paul; Wenjie Luo
• Keywords: Lipopolysaccharides; 0301 basic medicine; Interleukin-1beta; 610; Mice, Transgenic; tau Proteins; Transgenic; Mice; 03 medical and health sciences; Apolipoproteins E; 0302 clinical medicine; Alzheimer Disease; 616; Medicine and Health Sciences; Animals; Humans; RC346-429; Psychiatry; Inflammation; Amyloid beta-Peptides; Research; Interleukin-1β; Hydroxycholesterols; Frontal Lobe; 3. Good health; Lipid metabolism; Steroid Hydroxylases; Apolipoprotein E; Neurology. Diseases of the nervous system; Microglia; Alzheimer’s disease

Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular chemical mediators neuroinflammation remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling immunity. Cholesterol 25-hydroxylase (CH25H), enzyme responsible for 25-HC production, has also been found be one disease-associated microglial (DAM) genes that are upregulated brain transgenic mouse models. We used real-time PCR immunoblotting examine CH25H expression human tissue tissue-bearing amyloid-β plaques or tau pathology. immune response primary microglia under different treatment conditions bearing genetic backgrounds was analyzed using ELISA, western blotting, immunocytochemistry. Treatment toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates stimulates secretion microglia. LPS-induced production pro-inflammatory cytokine IL-1β potentiated attenuated deletion CH25H. Microglia expressing apolipoprotein E4 (apoE4), a risk factor AD, produce greater amounts than apoE3-expressing following LPS. Remarkably, results level LPS-activated apoE4-expressing apoE2- Blocking potassium efflux inhibiting caspase-1 prevents 25-HC-potentiated release microglia, indicating involvement inflammasome activity. may function as microglial-secreted inflammatory mediator brain, promoting IL-1β-mediated apoE isoform-dependent manner (E4>>E2/E3) thus AD.