Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury. Issue 9 (13th October 2017)

• Record Type: Journal Article
• Authors: Mittal, Manish; Nepal, Saroj; Tsukasaki, Yoshikazu; Hecquet, Claudie M.; Soni, Dheeraj; Rehman, Jalees; Tiruppathi, Chinnaswamy; Malik, Asrar B.
• Is Part Of: Circulation research. Volume 121:Issue 9(2017)
• Publication Date: 2017-10-13
• Subjects: inflammation -- lung injury -- PARP-1 -- PMN transmigration -- TRPM2; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.117.311747
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: : TRPM2 (transient receptor potential melastatin-2) expressed in endothelial cells (ECs) is a cation channel mediating Ca 2+ entry in response to intracellular generation of adenosine diphosphoribose—the TRPM2 ligand. Objective: : Because polymorphonuclear neutrophils (PMN) interaction with ECs generates reactive oxygen species, we addressed the possible role of TRPM2 expressed in ECs in the mechanism of transendothelial migration of PMNs. Methods and Results: : We observed defective PMN transmigration in response to lipopolysaccharide challenge in adult mice in which the EC expressed TRPM2 is conditionally deleted ( Trpm2 iΔEC ). PMN interaction with ECs induced the entry of Ca 2+ in ECs via the EC-expressed TRPM2. Prevention of generation of adenosine diphosphoribose in ECs significantly reduced Ca 2+ entry in response to PMN activation of TRPM2 in ECs. PMNs isolated from gp91phox −/− mice significantly reduced Ca 2+ entry in ECs via TRPM2 as compared with wild-type PMNs and failed to induce PMN transmigration. Overexpression of the adenosine diphosphoribose insensitive TRPM2 mutant channel (C1008→A) in ECs suppressed the Ca 2+ entry response. Further, the forced expression of TRPM2 mutant channel (C1008→A) or silencing of poly ADP-ribose polymerase in ECs of mice prevented PMN transmigration. Conclusions: : Thus, endotoxin-induced transmigration of PMNs was secondary to TRPM2-activated Ca 2+ signaling and VE-cadherin phosphorylation resulting in the disassembly of adherens junctions and opening of the paracellular pathways. These results suggest blocking TRPM2 activation in ECs is a potentially important means of therapeutically modifying PMN-mediated vascular inflammation. Abstract : Supplemental Digital Content is available in the text.