NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Kyungho Kim, Jing Li, Alan Tseng, Robert Keith Andrews, Jaehyung Cho

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Abstract

Platelet-leukocyte interactions on activated endothelial cells play an important role during microvascular occlusion under oxidative stress conditions. However, it remains poorly understood how neutrophil-platelet interactions are regulated during vascular inflammation. By using intravital microscopy with mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their bone marrow chimera, we demonstrated that NOX2 from both hematopoietic and endothelial cells is crucial for neutrophil-platelet interactions during tumor necrosis factor alpha-induced venular inflammation. Platelet NOX2-produced reactive oxygen species (ROS) regulated P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Iba. Furthermore, neutrophil NOX2-generated ROS enhanced the activation and ligand-binding activity of aMb2 integrin following N-formyl-methionyl-leucyl phenylalanine stimulation. Studies with isolated cells and a mouse model of hepatic ischemia/reperfusion injury revealed that NOX2 from both platelets and neutrophils is required for cell-cell interactions, which contribute to the pathology of hepatic ischemia/reperfusion injury. Platelet NOX2 modulated intracellular Ca2+ release but not store-operated Ca2+ entry (SOCE), whereas neutrophil NOX2 was crucial for SOCE but not intracellular Ca2+ release. Different regulation of Ca2+ signaling by platelet and neutrophil NOX2 correlated with differences in the phosphorylation of AKT, ERK, and p38MAPK. Our results indicate that platelet and neutrophil NOX2-producedROSare critical for the function of surface receptors essential for neutrophil-platelet interactions during vascular inflammation.
Original languageEnglish
Pages (from-to)1952 - 1964
Number of pages13
JournalBlood
Volume126
Issue number16
DOIs
Publication statusPublished - 2015

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