β-Hydroxybutyrate inhibits the spontaneous apoptosis of neutrophils through a degranulation-macrophage-1 antigen axis in cows with subclinical ketosis.

Subclinical ketosis (SCK), a common metabolic disorder in dairy cows during the peripartum period, is accompanied by systemic inflammation and elevated circulating BHB. β-Hydroxybutyrate contributes to the development of systemic inflammation by inhibiting the spontaneous apoptosis of neutrophils in SCK cows. However, the underlying molecular mechanism is still unclear. This study investigated the role of the degranulation-macrophage-1 antigen (Mac-1) axis in this process. The results demonstrated that BHB promoted the degranulation process and activated membrane Mac-1 (CD11b/CD18) on neutrophils both ex vivo and in vitro. Neutrophils were isolated from healthy cows and treated with 2 mM BHB, a specific degranulation inhibitor, or a Mac-1 blocking antibody in vitro. We found that the released granule contents during degranulation activated the intracellular Mac-1 signaling pathway, which was involved in BHB-mediated inhibition of bovine neutrophil apoptosis. Overall, our findings reveal that the degranulation-Mac-1 axis plays a critical role in regulating BHB-induced inhibition of spontaneous neutrophil apoptosis in dairy cows with SCK.