title: Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis.
abstract: Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies.
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom; g.d.healey@swansea.ac.uk.
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Healey
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom;
authors.forename: Christine
authors.initials: C
authors.lastname: Collier
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom;
authors.forename: Sholeem
authors.identifier: http://orcid.org/0000-0003-0038-6399
authors.initials: S
authors.lastname: Griffin
authors.affiliation: University of Veterinary Medicine, 30559 Hannover, Germany;
authors.forename: Hans-Joachim
authors.identifier: http://orcid.org/0000-0002-5904-5751
authors.initials: HJ
authors.lastname: Schuberth
authors.affiliation: INRA, UMR 1198 Biologie du Développement et Reproduction, F-78350 Jouy-en-Josas, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Sandra
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; Moredun Research Institute, Midlothian EH26 0PZ, United Kingdom;
authors.forename: David G
authors.initials: DG
authors.lastname: Smith
authors.affiliation: Zoetis, Kalamazoo, MI 49007; and.
authors.forename: Suman
authors.initials: S
authors.lastname: Mahan
authors.affiliation: Zoetis, 75014 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dieuzy-Labaye
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom;
authors.forename: I Martin
authors.identifier: http://orcid.org/0000-0001-7902-5558
authors.initials: IM
authors.lastname: Sheldon
mesh_terms: D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000096:biosynthesis; D004195:Disease Models, Animal; D004716:Endometritis / Q000276:immunology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D008798:Mevalonic Acid / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D002784:Cholesterol; D008798:Mevalonic Acid