Mevalonate biosynthesis intermediates are key regulators of innate immunity in bovine endometritis

Healey, G. D., Collier, C., Griffin, S., Schuberth, H.-J., Sandra, O., Smith, D. G., Mahan, S., Dieuzy-Labaye, I. and Sheldon, I. M. (2016) Mevalonate biosynthesis intermediates are key regulators of innate immunity in bovine endometritis. Journal of Immunology, 196(2), pp. 823-831. (doi: 10.4049/jimmunol.1501080) (PMID:26673142) (PMCID:PMC4705593)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor David
• Authors: Healey, G. D., Collier, C., Griffin, S., Schuberth, H.-J., Sandra, O., Smith, D. G., Mahan, S., Dieuzy-Labaye, I., and Sheldon, I. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Immunology
• Publisher: American Association of Immunologists
• ISSN: 0022-1767
• ISSN (Online): 1550-6606
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Journal of Immunology 196(2):823-831
• Publisher Policy: Reproduced under a Creative Commons License