TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Yamamoto, Shinichiro; Shimizu, Shunichi; Kiyonaka, Shigeki; Takahashi, Nobuaki; Wajima, Takaaki; Hara, Yuji; Negoro, Takaharu; Hiroi, Toshihito; Kiuchi, Yuji; Okada, Takaharu; Kaneko, Shuji; Lange, Ingo; Fleig, Andrea; Penner, Reinhold; Nishi, Miyuki; Takeshima, Hiroshi; Mori, Yasuo

doi:10.1038/nm1758

Cited by 548 publications

(587 citation statements)

References 53 publications

(81 reference statements)

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“…Although not described in β-cells, a role for TRPM2 has been described in the inflammation through up-regulation of chemokines [42]. Inhibition of TRPM2 channels indeed prevents inflammation in a mouse model of colitis and inflammatory and neuropathic pain [42,43].…”

Section: Discussionmentioning

confidence: 99%

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

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Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca 2 + . Recent studies however revealed that TRPM2 channels can also conduct Zn 2 + , but the physiological relevance of this property is enigmatic. Given that Zn 2 + is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn 2 + to affect cell viability. To address this, we used the insulin secreting (INS1) β-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H 2 O 2 activation of TRPM2 channels increases the cytosolic levels of both Ca 2 + and Zn 2 + and causes apoptotic cell death. Interestingly, chelation of Zn 2 + alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn 2 + is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn 2 + release. Zn 2 + release is potentiated by extracellular Ca 2 + entry, indicating that Ca 2 + -induced Zn 2 + release leads to apoptosis. Knockout of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca 2 + -potentiated Zn 2 + release underlies ROS-induced β-cell death and Zn 2 + , rather than Ca 2 + , plays a primary role in apoptosis.

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Section: Discussionmentioning

confidence: 99%

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

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“…While human neutrophils are responsive to CCK stimulation, the physiological effect seems rather immunosuppressive than stimulatory in nature [38]. In contrast, a recent report emphasizes the key role of ROS-induced TRPM2 activation in aggravating chemokine-initiated neutrophil infiltration [39].…”

Section: Discussionmentioning

confidence: 99%

Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophils

et al. 2008

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SummaryThe Ca 2+ -permeable TRPM2 channel is a dual function protein that is activated by intracellular ADPR through its enzymatic pyrophosphatase domain with Ca 2+ acting as a co-factor. Other TRPM2 regulators include cADPR, NAADP and H 2 O 2 , which synergize with ADPR to potentiate TRPM2 activation. Although TRPM2 has been thoroughly characterized in overexpression or cell-line systems, little is known about the features of TRPM2 in primary cells. We here characterize the regulation of TRPM2 activation in human neutrophils and report that ADPR activates TRPM2 with an effective half-maximal concentration (EC 50 ) of 1 μM. Potentiation by Ca 2+ is dose-dependent with an EC 50 of 300 nM. Both cADPR and NAADP activate TRPM2, albeit with lower efficacy than in the presence of subthreshold levels of ADPR (100 nM), which significantly shifts the EC 50 for cADPR from 44 μM to 3 μM and for NAADP from 95 μM to 1 μM. TRPM2 activation by ADPR can be suppressed by AMP with an IC 50 of 10 μM and cADPR-induced activation can be blocked by 8-Bromo-cADPR. We further show that 100 μM H 2 O 2 enables subthreshold concentrations of ADPR (100 nM) to activate TRPM2. We conclude that agonistic and antagonistic characteristics of TRPM2 as seen in overexpression systems are largely compatible with the functional properties of TRPM2 currents measured in human neutrophils, but the potencies of agonists in primary cells are significantly higher.

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“…TRPM2 KO mice 28 were bred in-house and used at 9 to 10 weeks of age (20 to 30 g). Wild-type C57Bl/6 mice (males and 1 females, 9 to 10 weeks of age, weighing 20 to 30 g) were purchased from Charles River Laboratories (Wilmington, MA, USA).…”

Section: Experimental Animalsmentioning

confidence: 99%

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

Shimizu

Macey

Quillinan

et al. 2013

J Cereb Blood Flow Metab

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The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.

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TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Cited by 548 publications

References 53 publications

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophils

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

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