TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection

Beceiro, Susana; Radin, Jana N.; Chatuvedi, R; Piazuelo, M. Blanca; Horvarth, D J; Cortado, Hanna; Gu, Yuanzheng; Dixon, Beverly R. E. A.; Gu, Chen; Lange, Ingo; Koomoa, D-Lt; Wilson, Keith T.; Algood, Holly M. Scott; Partida-Sánchez, Santiago

doi:10.1038/mi.2016.60

Cited by 65 publications

(54 citation statements)

References 57 publications

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“…9 Furthermore, a recent study indicated that intracellular Ca2 + overloading triggers greater macrophage production of inflammatory mediators and promotes classically activated macrophage M1 polarization. 34 In the present study, we found that decreasing STAT-1 phosphorylation underscores the role of blocking KCa3.1 in inhibiting proinflammatory genes expression during macrophage polarization and attenuating plaque instability. However, further study is needed to understand the mechanisms that underlie the interplay between KCa3.1 and JAK/STAT signaling in detail.…”

Section: Discussionmentioning

confidence: 60%

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

et al. 2017

ATVB

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Objective-Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Approach and Results-Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. opening, which results in K + efflux that maintains a negative membrane potential. Thus, the initial influx of Ca 2+ feeds forward, thereby, preserving the negative V m (membrane voltage) required for sustained Ca 2+ influx. 12 The Ca 2+ influx leads to an increase in cytosolic Ca 2+ concentration, which is necessary for the translocation of nuclear factors to the nucleus and the initiation of new transcription. Conclusions-TheseParticularly, in macrophages, KCa3.1 has been shown to be involved in activation, migration, proliferation, and respiratory bursting, indicating that KCa3.1 suppression might be helpful in some macrophage-related disorders, such as asthma, multiple sclerosis, stroke, and so forth. [13][14][15] Previous evidence has demonstrated a role for KCa3.1 in atherosclerosis. In mouse models, pharmacological inhibition of KCa3.1 by the selective blocker TRAM-34 attenuates atherosclerotic lesion formation and may provide a novel approach for the prevention and treatment of atherosclerosis. 16 However, in advanced atherosclerotic lesions, the role of KCa3.1 in the pathogenesis of plaque instability and its underlying mechanisms are unknown. A recent study reported that IL-4 stimulation increases KCa3.1 current in microglia, 17 which suggests that KCa3.1 may be involved in the polarization of macrophages and atherosclerotic plaque disruption. In this study, we pharmacologic...

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Section: Discussionmentioning

confidence: 60%

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

et al. 2017

ATVB

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“…Mixed populations of pro-and anti-inflammatory M1 and M2 macrophages, respectively, were reported to be present in the gastric mucosa of H. pylori-infected individuals [32][33][34]. To test their importance, peripheral blood monocytes were isolated from three volunteers and differentiated to M1 and M2 macrophages, which was confirmed by flow cytometric analysis of overexpression of M1 markers (CD40 and CD86) and M2 markers (CD163 and CD204) ( Figure 4A).…”

Section: Activation Of Nlrp3 Inflammasome In Human Primary M1 and M2mentioning

confidence: 76%

Helicobacter pylori Avoids the Critical Activation of NLRP3 Inflammasome-Mediated Production of Oncogenic Mature IL-1β in Human Immune Cells

Pachathundikandi

Blaser

Bruns

et al. 2020

Cancers

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Helicobacter pylori persistently colonizes the human stomach, and is associated with inflammation-induced gastric cancer. Bacterial crosstalk with the host immune system produces various inflammatory mediators and subsequent reactions in the host, but not bacterial clearance. Interleukin-1β (IL-1β) is implicated in gastric cancer development and certain gene polymorphisms play a role in this scenario. Mature IL-1β production depends on inflammasome activation, and the NLRP3 inflammasome is a major driver in H. pylori-infected mice, while recent studies demonstrated the down-regulation of NLRP3 expression in human immune cells, indicating a differential NLRP3 regulation in human vs. mice. In addition to the formation of mature IL-1β or IL-18, inflammasome activation induces pyroptotic death in cells. We demonstrate that H. pylori infection indeed upregulated the expression of pro-IL-1β in human immune cells, but secreted only very low amounts of mature IL-1β. However, application of exogenous control activators such as Nigericin or ATP to infected cells readily induced NLRP3 inflammasome formation and secretion of high amounts of mature IL-1β. This suggests that chronic H. pylori infection in humans manipulates inflammasome activation and pyroptosis for bacterial persistence. This inflammasome deregulation during H. pylori infection, however, is prone to external stimulation by microbial, environmental or host molecules of inflammasome activators for the production of high amounts of mature IL-1β and signaling-mediated gastric tumorigenesis in humans.

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“…It has previously been shown that IFN-γ-producing T cells are induced by IL-12 [17], and that mascrophages are potent producers of IL-12 at sites of bacterial infection [18]. Since macrophages have previously been implicated in H. pylori gastritis [19], and we next were interested to learn whether ADM-regulated macrophages would affect IFN-γ-producing T-cell responses via IL-12 during H. pylori infection. To begin, we found that an expression of ADM receptor domain protein, RAMP2, merged with CD68 staining on macrophages in H. pylori -infected gastric mucosa (Fig 6A and S5A Fig).…”

Section: Resultsmentioning

confidence: 99%

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Zhuang

Kong

Zhang

et al. 2018

Preprint

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23Abbreviations used in this paper: Helicobacter pylori, H. pylori; adrenomedullin, ADM; interleukin, IL; 24 interferon, IFN; receptor activity modifying protein, RAMP; phosphoinositide 3-kinase, PI3K; signal 25 transducers and activators of transcription, STAT; wild-type, WT; knockout, KO; post infection, p.i.; 26 haematoxylin and eosin, H&E.Abstract 2 Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, 3 but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric ADM 4 expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. 5 pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of 6 gastritis, accordingly, blockade of ADM resulted in decreased inflammation within the gastric 7 mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via 8 PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and 9 resulted in increased inflammation within the gastric mucosa. This inflammation was characterized 10 by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation 11 of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to 12 produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the 13 development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ 14 decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a 15 novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and 16 IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.17 18 Author summary 19 H. pylori infect almost half the world's population. Once infected, most of people carry the bacteria 20 lifelong if left untreated, so that persistent H. pylori infection can lead to chronic gastritis, peptic 21 ulceration and ultimately gastric cancer. H. pylori infection is accompanied with increased 22 inflammation in gastric mucosa, but the mechanisms of chronic gastritis induced by H. pylori 23 infection remains poorly understood. We studied a multifunctional peptide known as adrenomedullin 24 (ADM) in gastric epithelial cells, which was known as a key factor of regulating gastrointestinal 25 physiology and pathology. Here, we found that gastric ADM expression was elevated in gastric 26 mucosa of H. pylori-infected patients and mice, and was positively correlated with the degree of 27 gastritis. ADM production was promoted via PI3K-AKT signaling pathway activation by gastric 28 epithelial cells in a cagA-dependent manner. Blockade of ADM during H. pylori infection resulted in 29 decreased gastric inflammation that was characterized by the increased IFN-γ-producing T cells 30 which was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric 1 epitheli...

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TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection

Cited by 65 publications

References 57 publications

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

Helicobacter pylori Avoids the Critical Activation of NLRP3 Inflammasome-Mediated Production of Oncogenic Mature IL-1β in Human Immune Cells

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

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