Equine Neutrophils Respond to PGE2 by Activating Expression of Core Circadian Clock Genes

Abstract

An emerging body of evidence supports a relationship between the circadian and immune systems during an innate immune response. Previously, we have demonstrated synchronized upregulation of core circadian clock genes, Per2 and Bmal1, in equine whole blood following lipopolysaccharide (LPS) administration in vivo. Subsequent experi- ments suggested a role for the febrile mediator, prostaglandin E2 (PGE2), in mediating this response. However, PGE2 failed to directly stimulate clock gene expression in equine PBMCs. This study demonstrates that ex vivo cultured equine neutrophils actively respond to PGE2 by upregulating Per2 and Bmal1 expression. In addition, we show that LPS induces marked neutrophilia and concomitant monocytopenia in equine peripheral blood at the time corresponding to the previ- ously observed clock gene rise. We further report that the peak in the PGE2 mediated endotoxic fever also occurs simulta- neously. Combined, our data suggest that neutrophils are the source of the rise in Per2 and Bmal1 expression previously observed in equine peripheral blood following LPS administration, and that this response is likely mediated by PGE2. These results provide the first evidence for a potential role of core circadian clock genes in neutrophil function following innate immune activation.