| Autor: |
Yeudall S; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Upchurch CM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Seegren PV; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Pavelec CM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Greulich J; Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany., Lemke MC; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Harris TE; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Desai BN; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Hoehn KL; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia., Leitinger N; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. |
| Abstrakt: |
Acetyl-CoA carboxylase (ACC) regulates lipid synthesis; however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow-derived macrophages, resulting in a blunted response to proinflammatory stimulation. In response to lipopolysaccharide (LPS), ACC is required for the early metabolic switch to glycolysis and remodeling of the macrophage lipidome. ACC deficiency also resulted in impaired macrophage innate immune functions, including bacterial clearance. Myeloid-specific deletion or pharmacological inhibition of ACC in mice attenuated LPS-induced expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, while pharmacological inhibition of ACC increased susceptibility to bacterial peritonitis in wild-type mice. Together, we identify a critical role for ACC in metabolic regulation of the innate immune response in macrophages, and thus a clinically relevant, unexpected consequence of pharmacological ACC inhibition. |
