The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Autor:	Clayton SA; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK., Lockwood C; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., O'Neil JD; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Daley KK; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Hain S; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK., Abdelmottaleb D; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.; Zoology Department, Faculty of Science, Benha University, Benha, Egypt., Bolimowska OO; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Tennant DA; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK., Clark AR; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
Jazyk:	angličtina
Zdroj:	Discovery immunology [Discov Immunol] 2023 Dec 04; Vol. 2 (1), pp. kyad027. Date of Electronic Publication: 2023 Dec 04 (Print Publication: 2023).
DOI:	10.1093/discim/kyad027
Abstrakt:	Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization. Competing Interests: D.A.T. has undertaken paid consultancy work with Sitryx. Other authors declare that they have no conflicts of interest. (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)
Databáze:	MEDLINE
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