Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

Abstract

G protein-coupled receptor (GPR)109A (HM74A) is a G i protein-coupled receptor, which is activated by nicotinic acid (NA), a lipidlowering drug. Here, we demonstrate that mature human neutrophils, but not eosinophils, express functional GPR109A receptors. The induction of the GPR109A gene appears to occur late in the terminal differentiation process of neutrophils, since a mixed population of immature bone marrow neutrophils did not demonstrate evidence for its expression. NA accelerated apoptosis in cultured neutrophils in a concentration-dependent manner, as assessed by phosphatidylserine redistribution, caspase-3 activation, and DNA fragmentation assays. The pro-apoptotic effect of NA was abolished by pertussis toxin, which was used to block G i proteins, suggesting a receptor-mediated mechanism. Activation of GPR109A by NA resulted in decreased levels of cyclic adenosine monophosphate (cAMP), most likely due to G i -mediated inhibition of adenylyl cyclase activity. NAinduced apoptosis was reversed by the addition of cell-permeable cAMP, pointing to the possibility that reduced cAMP levels promote apoptosis in neutrophils. Distal mechanism involved in this process may include the post-translational modification of members of the Bcl-2 family, such as dephosphorylation of pro-apoptotic Bad and antiapoptotic Mcl-1 proteins. Taken together, following maturation in the bone marrow, neutrophils express functional GPR109A receptors, which might be involved in the regulation of neutrophil numbers. Moreover, this study identified a new cellular target of NA and future drugs activating GPR109A receptors, the mature neutrophil.

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

“…Our present finding support this, as addition of a Ca 2 þ chelator to epithelial cells blocked the hyperpolarizing effects of acetate. Similar to GPR43, activation of other SCFA receptors such as GPR41 and GPR109A induces intracellular Ca 2 þ mobilization in neutrophils 33,37 , and presumably the same occurs in colonic epithelial cells, resulting in inflammasome activation and gut homeostasis. This might explain why highfibre feeding still had a beneficial role in Gpr43 À / À and Gpr109A À / À mice.…”

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

“…14). The activation of HCA 2 inhibits adhesion and migration of neutrophils and induces the death of these cells in vitro 38,39 . Whether modulation of neutrophils contributes to the neuroprotective effects of HCA 2 in cerebral ischemia is still unclear.…”

CXCR4 Chemokine Receptor Signaling Induces Apoptosis in Acute Myeloid Leukemia Cells via Regulation of the Bcl-2 Family Members Bcl-XL, Noxa, and Bak

“…Signaling by G i -type G proteins has previously been shown to induce apoptosis in hepatocytes and neutrophils (54,55), and CXCR4 is able to signal through G i -type G proteins in response to SDF-1 (25,48,56). To address whether CXCR4 utilizes G itype G proteins to induce apoptosis, we treated KG1a-CXCR4 cells with pertussis toxin (PTX), an exotoxin that inhibits G itype G proteins.…”