11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation

• Published in: Brain, behavior, and immunity behavior, and immunity, 2018-03, Vol.69, p.223-234
• Main Authors: Verma, Manu, Kipari, Tiina M.J., Zhang, Zhenguang, Man, Tak Yung, Forster, Thorsten, Homer, Natalie Z.M., Seckl, Jonathan R., Holmes, Megan C., Chapman, Karen E.
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11β-hydroxysteroid dehydrogenase; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Corticosterone - blood; Energy metabolism; Energy Metabolism - physiology; Glucocorticoid metabolism; Glycolysis; Hippocampus - drug effects; Hippocampus - metabolism; Illness Behavior - drug effects; Illness Behavior - physiology; Inflammation; Inflammation - genetics; Inflammation - metabolism; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Monocytes - metabolism; Neutrophils - metabolism
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.11.015

•11β-HSD1-deficiency reduces the hippocampal inflammatory response to LPS.•This happens despite similar peripheral inflammation.•11β-HSD1-deficiency favours a “Warburg” like response to LPS in the hippocampus.•LPS increases hippocampal fumarate levels in 11β-HSD1-deficient mice.•Fumarate accumulation can cause pseudo-hypoxia. Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.