Abstract
Elevated plasma concentrations of the ketone body β-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows. In the early stages of this pathology, an increase in neutrophil recruitment is observed; however, the role of BHB remains elusive. This study characterized the effect of BHB and synthetic agonists of the HCA2 receptor on bovine neutrophil chemotaxis and the signaling pathways involved in this process. We demonstrated that treatment with BHB concentrations between 1.2 and 10 mM and two full selective agonists of the HCA2 receptor, MK-1903 and nicotinic acid, increased bovine neutrophil chemotaxis. We also observed that BHB and HCA2 agonists induced calcium release and phosphorylation of AKT, ERK 1/2 and AMPKα. To evaluate the role of these pathways in bovine neutrophil chemotaxis, we used the pharmacological inhibitors BAPTA-AM, pertussis toxin, U73122, LY294002, U0126 and compound C. Our results suggest that these pathways are required for HCA2 agonist-induced bovine neutrophil chemotaxis in non-physiological condition. Concentrations around 1.4 mM of BHB after calving may exert a chemoattractant effect that is key during the onset of the inflammatory process associated with metabolic disorders in dairy cows.
Highlights
Elevated plasma concentrations of the ketone body β-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows
We observed a significant increase in bovine neutrophils chemotaxis at concentration ≥ 1.2 mM BHB (Fig. 1A,B)
We evaluated expression of the HCA2 receptor in bovine neutrophils and kidney adipose tissue used as a positive control by real-time PCR using specific primers for HCA2
Summary
Elevated plasma concentrations of the ketone body β-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows. Stimulation of the G protein complex causes the activation of phospholipase Cβ (PLCβ), which results in an increase in intracellular calcium levels[5] These molecules initiate a cascade of events that produce rapid changes in the cytoskeleton and neutrophil shape, resulting in cell polarization[6]. Another study showed that leukocytes from ketotic cows obtained by 4-day feed restriction were not impaired in their chemotactic c apacity[13] Until now, it has been unclear whether bovine neutrophil chemotaxis is altered by BHB and which intracellular signaling pathways are involved in these processes. This receptor was initially identified as the receptor of the antidyslipidemic and antiatherogenic drug nicotinic a cid[15,16,17] and later as the receptor for the free fatty acid (FFA) b utyrate[18]
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