Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation

Wang, Gang; Cao, Luyang; Liu, Xiaowen; Sieracki, Nathan A.; Di, Anke; Wen, Xian‐Huan; Chen, Yong; Taylor, Shalina; Huang, Xiaodan; Tiruppathì, Chinnaswamy; Zhao, You Yang; Song, Yuanlin; Gao, Xiaopei; Jin, Tian; Bai, Chunxue; Malik, Asrar B.; Xu, Jingsong

doi:10.1016/j.devcel.2016.07.014

Cited by 57 publications

(68 citation statements)

References 52 publications

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“…TRPM2 is highly expressed in ECs where it plays an important role in regulating key functions of the endothelium in innate immunity (21–23), endothelial barrier (3, 14, 24), and EC apoptosis (25). We observed that conditional deletion of TRPM2 in ECs ( Trpm2 iΔEC ) of mice markedly reduced PMN transmigration and sequestration in tissue.…”

Section: Discussionmentioning

confidence: 99%

“…TRPM2, a.k.a TRPC7 and LTRPC-2, is a non-selective cation channel expressed in mammalian tissue, including endothelial cells, blood cells such as PMNs, bone marrow cells, brain, spleen, heart, liver, and lungs (5). Expression of TRPM2 in macrophages and PMNs is important in regulating the bactericidal activity of phagocytic cells and PMN migration in tissue (6, 7). The binding of the intracellular second messenger adenosine diphosphoribose (ADPR) or related molecules to the Nudix box sequence motif (NUDT9-H) in its carboxyl-terminal domain regulates the gating of TRPM2 channel after exposure to oxidants (8–10).…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury

Mittal

Nepal

Tsukasaki

et al. 2017

Circulation Research

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Rationale TRPM2 (Transient Receptor Potential Melastatin-2) expressed in endothelial cells (ECs) is a cation channel mediating Ca2+ entry in response to intracellular generation of adenosine diphosphoribose (ADPR), the TRPM2 ligand. Objective Because polymorphonuclear leukocytes (PMN) interaction with endothelial cells (ECs) generates ROS, 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 LPS challenge in adult mice in which the EC expressed TRPM2 is conditionally deleted (Trpm2iΔEC). PMN interaction with ECs induced the entry of Ca2+ in ECs via the EC-expressed TRPM2. Prevention of generation of ADPR in ECs significantly reduced Ca2+ entry in response to PMN activation of TRPM2 in ECs. PMNs isolated from gp91phox−/− mice significantly reduced Ca2+ entry in ECs via TRPM2 as compared to WT PMNs and failed to induce PMN transmigration. Overexpression of the ADPR insensitive TRPM2 mutant channel (C1008→A) in ECs suppressed the Ca2+ entry response. Further the forced expression of TRPM2 C1008→A mutant channel or silencing of PARP-1 in ECs of mice prevented PMN transmigration. Conclusion Thus, endotoxin-induced transmigration of PMNs was secondary to TRPM2-activated Ca2+ 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury

Mittal

Nepal

Tsukasaki

et al. 2017

Circulation Research

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“…Members of the TRPM family are monovalent‐cation channels, characterized by a variable selectivity for divalent ions . TRPM2, for instance is permeable for Ca 2+ and is the only member of the TRPM family known to be expressed on human and murine neutrophils . TRPM2 may play an important role as a stress sensor, translating metabolic and oxidative signals into Ca 2+ flux .…”

Section: Other Ion Channels Involved In Ca2+ Signalling In Neutrophilsmentioning

confidence: 99%

“…Further evidence for a specific role of TRPM2 in fMLF‐induced signalling comes from the observation that in hPMNs, TRPM2 acts exclusively downstream of FPRs . Moreover, TRPM2 may restrain neutrophil migration, as the channel is internalized together with FPR1 at the site of infection, hence permitting and initiating neutrophil‐mediated host defence, namely phagocytosis and secretion of antimicrobial agents …”

Section: Other Ion Channels Involved In Ca2+ Signalling In Neutrophilsmentioning

confidence: 99%

“…56 TRPM2, for instance is permeable for Ca 2+ and is the only member of the TRPM family known to be expressed on human and murine neutrophils. 54,56,63 TRPM2 may play an important role as a stress sensor, translating metabolic and oxidative signals into Ca 2+ flux. 64 This channel is activated by ADP ribose (ADPR), cyclic ADPR (cADPR), adenosine monophosphate (AMP), nicotinic acid adenine dinucleotide phosphate (NAADP) and by hydrogen peroxide (H 2 O 2 ).…”

Section: Trp Channelsmentioning

confidence: 99%

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Calcium signalling and related ion channels in neutrophil recruitment and function

Immler

Simon

Sperandio

2018

Eur J Clin Investigation

115

108

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The recruitment of neutrophils to sites of inflammation, their battle against invading microorganisms through phagocytosis and the release of antimicrobial agents is a highly coordinated and tightly regulated process that involves the interplay of many different receptors, ion channels and signalling pathways. Changes in intracellular calcium levels, caused by cytosolic Ca store depletion and the influx of extracellular Ca via ion channels, play a critical role in synchronizing neutrophil activation and function. In this review, we provide an overview of how Ca signalling is initiated in neutrophils and how changes in intracellular Ca levels modulate neutrophil function.

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Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production

Okochi

Umemoto

Okamura

2020

Journal of Leukocyte Biology

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High-level reactive oxygen species (ROS) production in neutrophils is tightly regulated, as it can damage host cells. Neutrophils also undergo low-level ROS production when stimulated by cytokines or chemoattractants, but its biologic significance remains largely unknown. Voltagegated proton channels (Hv1/VSOP) activity reportedly supports ROS production in neutrophils; however, we show here that Hv1/VSOP balances ROS production to suppress neutrophil directional migration in the presence of low concentrations of N-formyl-Met-Leu-Phe (fMLF).Neutrophils derived from Hvcn1 gene knockout mice produced more ROS than neutrophils from wild-type mice in the stimulation with fMLF at concentration of 1 µM and nonstimulus condition. They also exhibited stronger chemotactic responses to low concentrations of fMLF than did wild-type neutrophils. Receptor sensitivity to fMLF and evoked Ca 2+ responses did not differ between Hv1/VSOP-deficient and wild-type neutrophils. Activation of ERK, but not p38, was enhanced and prolonged during the increased ROS production seen after fMLF stimulation in Hv1/VSOP-deficient neutrophils. Inhibiting ROS production suppressed the enhanced ERK activation in Hv1/VSOP-deficient neutrophils and their directional migration. These results indicate that Hv1/VSOP balances ROS production to reduce ERK signaling and suppress excessive neutrophil migration in response to fMLF. Our findings thus reveal a novel role for ROS in the directional migration of neutrophils. K E Y W O R D S ERK, migration, proton channel, ROS INTRODUCTIONVoltage-gated proton channels (Hv1/VSOP) regulate a variety of cell functions, including T cell homeostasis, 1 BCR signaling, 2 sperm motility, 3 and pH regulation in airway epithelium. 4 However, the most extensively studied function of Hv1/VSOP is its positive regulation of reactive oxygen species (ROS) production in phagocytes. 2,5-7 Because the ROS generator NADPH oxidase transfers electrons across the cell membrane and releases protons inside the cell, its activity can lead to intracellular acidification and depolarization. 8 Hv1/VSOP offsets acidification and depolarization by mediating extrusion of intra-

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Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation

Cited by 57 publications

References 52 publications

Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury

Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury

Calcium signalling and related ion channels in neutrophil recruitment and function

Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production

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