Evidence is growing for the role of red blood cells (RBCs) in vascular homeostasis, including thrombogenic events and inflammation. Lysophosphatidic acid (LPA) is known to induce phosphatidylserine (PS) exposure and the release of RBC Extracellular Vesicles (REVs). Using high sensitivity flow cytometry, we examined the effects and the mechanisms by which the LPA species commonly found in human plasma could activate RBCs. We report that LPA 16:0, 18:0 and 18:1, but not LPA 20:4, induced PS exposure and the release of small PS and large PS REVs through LPA3 receptor signalling in RBCs. The release of large PS REVs required higher concentrations of LPA. RBCs were not activated by LPA 20:4. Interestingly, blockade of LPA2 enhanced LPAmediated PS REV release in RBCs. Furthermore, LPA receptor agonists and antagonists highlighted that LPA 20:4 inhibited LPA3-dependent PS exposure and, through the LPA2 receptor, inhibited PS REV production. Activation of RBCs with LPA 18:1 in normal plasma stimulated the release of PS and PS REVs. REVs released in response to LPA were similar to those found in the plasma of systemic lupus erythematosus patients. Our results suggest that LPA species exhibit different biological activities in RBCs through targeting LPA2 and/or LPA3 receptors.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.