Transient Receptor Potential Melastatin 2 Is Required for Lipopolysaccharide-Induced Cytokine Production in Human Monocytes

Wehrhahn, Janine; Kraft, Robert A.; Harteneck, Christian; Hauschildt, Sunna

doi:10.4049/jimmunol.0902474

Cited by 126 publications

(72 citation statements)

References 52 publications

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“…This notion is supported by the defective clearance of Lm in mice deficient in NF-κB (42), the importance of TRPM2 for LPS-induced TNFα production in human monocytes (14), as well as the attenuated NF-κB activation and reduced IL-12 and IFNγ expression during chemically induced colitis using a different TRPM2 −/− mouse strain (13). It is noteworthy that although it has been shown in the murine DSS colitis model that IL-6 production is mediated by NF-κB (p65) in the colon (43), DSS-treated TRPM2 −/− mice show no alterations in IL-6 levels (13).…”

Section: Discussionmentioning

confidence: 93%

“…Thus, IL-12-independent mechanisms that would normally compensate for IL-12 deficiency, such as TNFα or IL-18, are also affected in TRPM2 −/− mice. Indeed, it has been reported elsewhere that TRPM2 contributes to LPSinduced TNFα production in human monocytes (14) and such a TNFα deficiency would contribute to the elevated susceptibility in TRPM2…”

Section: Discussionmentioning

confidence: 94%

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Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenes

Knowles

Heizer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

108

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The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca 2+ -permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm ), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2 −/− mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2 −/− mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2 −/− mice displayed a higher degree of susceptibility than IL-12–unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm -infected TRPM2 −/− mice. The severity of listeriosis we observed in TRPM2 −/− mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenes

Knowles

Heizer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

108

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“…Although little is known about TRPM2, it has been hypothesized that TRPM2 is a type of non-selective cation channel that is permeable to Ca 2+ (18)(19)(20). Multiple molecules can activate TRPM2, including ADP-ribose and hydrogen peroxide.…”

Section: +mentioning

confidence: 99%

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Pang

Kim

et al. 2017

Exp Ther Med

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Abstract. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca 2+ permeable channel activated by cAMP, is expressed on pancreatic β-cells and is responsible for the regulation of insulin secretion. It is known that glucose-stimulated insulin secretion (GSIS) can be potentiated by glucagon like peptide-1 (GLP-1), and that the changes in the extracellular glucose concentration alter the levels of intracellular adenosine ATP and cAMP. The present study hypothesized that TRPM2 mediates the modulatory effect of GLP-1 on insulin secretion. The results demonstrated that silencing of TRPM2 eliminated GLP-1-enhanced insulin secretion, indicating the involvement of TRPM2 in this process. In addition, the results of current recordings of TRPM2 and measurement of the resulting insulin secretion in β-cells in the presence of GLP-1 and various concentrations of glucose suggest that GLP-1 regulates GSIS via the TRPM2 channel. Furthermore, inhibiting the activity or expression of TRPM2 attenuated GLP-1-induced GSIS. By using specific activators or inhibitors, the present study demonstrated that the two primary downstream effectors of the GLP-1 receptor, exchange protein directly activated by cAMP and protein kinase A, differentially influence GSIS and GLP-1-potentiated GSIS. In conclusion, the present study revealed the role of TRPM2 in GLP-1-regulated insulin secretion. The results of the present study provide a novel avenue for the prevention and treatment of diabetes and its complications. IntroductionPancreatic β-cells secrete insulin via insulin-containing granules that translocate from the intracellular insulin reservoir to the cell surface membrane, fuse with the membrane and secrete insulin through exocytosis (1,2 , and mediates ER-regulated membrane potential and insulin secretion (4). TRP family channels are non-selective cation channels in general, however some members are selective with with differential permeability to Ca 2+ (5). There are ~30 types of TRP channels that have been reported to be expressed on β-cells, including TRP vanilloid, TRP ankyrin, TRP canonical and TRP melastatin (TRPM) (6). Among these channels, TRPM2, a Ca 2+ -permeable channel, was demonstrated to be associated with glucose metabolism and insulin secretion, yet little is known about the underlying mechanisms of these associations (7).In recent years, glucagon like peptide 1 (GLP-1) and its analogues, also known as incretins, have attracted much attention for their anti-diabetic properties. A previous study demonstrated that incretins are secreted following a meal and promote insulin secretion, thereby minimizing the fluctuation of postprandial blood glucose concentrations (8). However, the 'incretin effect' in patients with type 2 diabetes

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“…In addition to PTCs (Figure 1), TRPM2 is expressed in other cell types including hematopoietic cells (13). TRPM2 has been reported to influence the response of neutrophils, monocytes, and dendritic cells to inflammation (13,35,36). Since inflammation is a mediator of I/R injury, it was possible that TRPM2 expressed on hematopoietic cells might account for the resistance of Trpm2-KO mice to kidney ischemia.…”

Section: Trpm2 Is Expressed In Kidney Proximal Tubulesmentioning

confidence: 99%

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

Gao¹,

Wang²,

Tadagavadi³

et al. 2014

J. Clin. Invest.

103

101

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Measurement of TBARs. The measurement of TBARS in the kidney was based on the formation of malondialdehyde (MDA) as described by Liu et al. (87).Statistics. All assays were performed in duplicate or triplicate. Data are reported as the means ± SEM. Statistical significance was assessed by an unpaired, 2-tailed Student's t test for single comparison or by ANOVA for multiple comparisons. P < 0.05 was considered statistically significant. GraphPad Prism (GraphPad Software) was used for statistical analyses and graphs.Study approval. All experiments involving mice were approved by the

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Transient Receptor Potential Melastatin 2 Is Required for Lipopolysaccharide-Induced Cytokine Production in Human Monocytes

Cited by 126 publications

References 52 publications

Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenes

Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenes

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

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