β-Hydroxybutyrate inhibits apoptosis in bovine neutrophils through activating ERK1/2 and AKT signaling pathways

Yuxiang Song, Kexin Wang, Juan J. Loor, Qianming Jiang, Yuchen Yang, Shang Jiang, Siyuan Liu, Jiyuan He, Xiancheng Feng, Xiliang Du, Lin Lei, Wenwen Gao, Guowen Liu, Xinwei Li

Research output: Contribution to journalArticlepeer-review

Abstract

Ketosis in dairy cows, a common metabolic disorder during the peripartal period, is accompanied by systemic inflammation and high concentrations of blood β-hydroxybutyrate (BHB). Neutrophil apoptosis plays a key role in maintaining the balance of inflammation and functional capacity of circulating neutrophils in ketotic cows. The kinases ERK1/2 and AKT, as well as their downstream Bcl-2 family-mediated mitochondrial signaling, are important apoptosis-regulating pathways in neutrophils. The objective of our study was to investigate the effects of BHB on neutrophil apoptosis and the underlying regulatory mechanisms during ketosis. Neutrophils were isolated from 5 multiparous cows (within 3 wk postpartum) with serum BHB concentrations <0.6 mM and glucose concentrations >3.5 mM. In a series of experiments, neutrophils were treated with increasing concentrations of BHB (0, 0.6, 2, and 3 mM for 10 h) and time (0, 2, 4, 6, 8, and 10 h with 2 mM). Subsequently, a 2 mM BHB dose was used to challenge neutrophils for 8 h. Apoptosis rate of neutrophils and protein abundance of cleaved caspase 3 were lower after BHB treatment. Treatment with BHB decreased protein and mRNA abundance of the pro-apoptotic genes Bax (BAX) and Bad (BAD), whereas it increased mitochondrial membrane potential (MMP) and protein and mRNA of the anti-apoptotic genes Bcl-xL (BCL2L1) and Mcl-1 (MCL1). This indicated that a mitochondrial pathway was involved in the inhibition of neutrophil apoptosis via BHB. In addition, both SCH772984 (an inhibitor of the ERK1/2 signaling pathway) and MK-2206 (an inhibitor of the AKT signaling pathway) alleviated the BHB-induced anti-apoptotic function of the Bcl-2 family and the inhibition of MMP. Overall, our data demonstrated that high concentrations of BHB inhibit apoptosis in bovine neutrophils by activating the ERK1/2 and AKT signaling pathways. These findings provide a theoretical basis for the understanding of systemic inflammation in ketotic cows.

Original languageEnglish (US)
Pages (from-to)3477-3489
Number of pages13
JournalJournal of Dairy Science
Volume105
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • apoptosis
  • dairy cow
  • neutrophils
  • β-hydroxybutyrate

ASJC Scopus subject areas

  • Food Science
  • Animal Science and Zoology
  • Genetics

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