Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity
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 occurr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2021.625347/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | John Quiroga |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T14:27:33Z |
| format | Article |
| id | doaj.art-a1b8a750c781478a97d1331d08dab6fb |
| institution | Directory Open Access Journal |
| issn | 2297-1769 |
| language | English |
| last_indexed | 2024-12-19T14:27:33Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj.art-a1b8a750c781478a97d1331d08dab6fb2022-12-21T20:17:34ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692021-03-01810.3389/fvets.2021.625347625347Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 ActivityJohn Quiroga0John Quiroga1Pablo Alarcón2Pablo Alarcón3Carolina Manosalva4Stefanie Teuber5Stefanie Teuber6Anja Taubert7Carlos Hermosilla8María Angélica Hidalgo9María Angélica Hidalgo10María Daniella Carretta11María Daniella Carretta12Rafael Agustín Burgos13Rafael Agustín Burgos14Laboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileFaculty of Sciences, Institute of Pharmacy, Universidad Austral de Chile, Valdivia, ChileLaboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileBiomedical Research Center Seltersberg, Institute of Parasitology, Justus Liebig University Giessen, Giessen, GermanyBiomedical Research Center Seltersberg, Institute of Parasitology, Justus Liebig University Giessen, Giessen, GermanyLaboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Inflammation Pharmacology, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileLaboratory of Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile, Valdivia, ChileAcute 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.https://www.frontiersin.org/articles/10.3389/fvets.2021.625347/fullbovine fibroblast-like synoviocyteD-lactatemetabolic reprogramminginflammationhypoxia inducible factor 1 |
| spellingShingle | 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 Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity Frontiers in Veterinary Science bovine fibroblast-like synoviocyte D-lactate metabolic reprogramming inflammation hypoxia inducible factor 1 |
| title | Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity |
| title_full | Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity |
| title_fullStr | Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity |
| title_full_unstemmed | Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity |
| title_short | Metabolic Reprogramming and Inflammatory Response Induced by D-Lactate in Bovine Fibroblast-Like Synoviocytes Depends on HIF-1 Activity |
| title_sort | metabolic reprogramming and inflammatory response induced by d lactate in bovine fibroblast like synoviocytes depends on hif 1 activity |
| topic | bovine fibroblast-like synoviocyte D-lactate metabolic reprogramming inflammation hypoxia inducible factor 1 |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2021.625347/full |
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