Frontiers in Veterinary Science (Mar 2021)

Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity

  • John Quiroga,
  • John Quiroga,
  • Pablo Alarcón,
  • Pablo Alarcón,
  • Carolina Manosalva,
  • Stefanie Teuber,
  • Stefanie Teuber,
  • Anja Taubert,
  • Carlos Hermosilla,
  • María Angélica Hidalgo,
  • María Angélica Hidalgo,
  • María Daniella Carretta,
  • María Daniella Carretta,
  • Rafael Agustín Burgos,
  • Rafael Agustín Burgos

DOI
https://doi.org/10.3389/fvets.2021.625347
Journal volume & issue
Vol. 8

Abstract

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Acute ruminal acidosis (ARA) occurs after an excessive intake of rapidly fermentable carbohydrates and is characterized by the overproduction of D-lactate in the rumen that reaches the bloodstream. Lameness presentation, one of the primary consequences of ARA in cattle, is associated with the occurrence of laminitis and aseptic polysynovitis. Fibroblast-like synoviocytes (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the chances of the release of pro-inflammatory cytokines. Increased D-lactate levels and disturbances in the metabolism of carbohydrates, pyruvates, and amino acids are observed in the synovial fluid of heifers with ARA-related polysynovitis prior to neutrophil infiltration, suggesting an early involvement of metabolic disturbances in joint inflammation. We hypothesized that D-lactate induces metabolic reprogramming, along with an inflammatory response, in bovine exposed FLS. Gas chromatography-mass spectrometry (GC-MS)-based metabolomics revealed that D-lactate disrupts the metabolism of bovine FLS, mainly enhancing glycolysis and gluconeogenesis, pyruvate metabolism, and galactose metabolism. The reverse-transcription quantitative PCR (RT-qPCR) analysis revealed an increased expression of metabolic-related genes, including hypoxia-inducible factor 1 (HIF-1)α, glucose transporter 1 (Glut-1), L-lactate dehydrogenase subunit A (L-LDHA), and pyruvate dehydrogenase kinase 1 (PDK-1). Along with metabolic disturbances, D-lactate also induced an overexpression and the secretion of IL-6. Furthermore, the inhibition of HIF-1, PI3K/Akt, and NF-κB reduced the expression of IL-6 and metabolic-related genes. The results of this study reveal a potential role for D-lactate in bFLS metabolic reprogramming and support a close relationship between inflammation and metabolism in cattle.

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