ABSTRACT
Mast cells and microglia play a critical role in innate immunity and inflammation and can be activated by a wide range of endogenous and exogenous stimuli. Lysophosphatidic acid (LPA) has recently been reported to activate mast cells and microglia. Using the human mast cell line HMC-1 and the mouse microglia cell line BV-2, we show that LPA-mediated activation can be prevented by blockade of the LPA receptorâ 5 (LPA5) in both cell lines. The identification of new LPA5-specific antagonists as tool compounds to probe and modulate the LPA5/LPA axis in relevant in vitro and in vivo assays should contribute to better understanding of the underlying role of LPAs in the development and progression of (neuro-) inflammatory diseases.
Subject(s)
Gene Expression/drug effects , Lysophospholipids/pharmacology , Receptors, Lysophosphatidic Acid/metabolism , Administration, Oral , Animals , Cell Line , Cell Membrane Permeability/drug effects , Chemokine CCL2/metabolism , Half-Life , Humans , Kinetics , Lysophospholipids/chemistry , Lysophospholipids/pharmacokinetics , Male , Mast Cells/cytology , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Mice, Inbred C57BL , Microglia/cytology , Microglia/drug effects , Microglia/metabolism , Microsomes, Liver/metabolism , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Receptors, Lysophosphatidic Acid/geneticsABSTRACT
Lysophosphatidic acid (LPA) is a potent activator of human platelets in vitro. Recently, the G protein-coupled receptor LPA5/GPR92 has been identified to be the relevant LPA receptor responsible for the activation of human platelets by LPA. In a high-throughput screening campaign we identified a diphenyl pyrazole carboxylic acid as a small-molecule inhibitor for LPA5. Confirmation for the specificity of this small molecule was achieved in human platelets as the relevant cellular in vitro model. We could confirm using antagonists for alternative LPA receptors that we identified in our work the first non-lipid, small-molecule inhibitor for LPA5/GPR92 specifically inhibiting LPA-mediated platelet activation in vitro.
