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

Gareth D. Healey, Christine Collier, Sholeem Griffin, Hans Joachim Schuberth, Olivier Sandra, David G. Smith, Suman Mahan, Isabelle Dieuzy-Labaye, I. Martin Sheldon

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)823-831
Number of pages9
JournalJournal of Immunology
Volume196
Issue number2
DOIs
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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