Calcium signalling and related ion channels in neutrophil recruitment and function

Immler, Roland; Simon, Scott I.; Sperandio, Markus

doi:10.1111/eci.12964

Cited by 116 publications

(115 citation statements)

References 99 publications

(234 reference statements)

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“…Calcium stored in the endoplasmic reticulum (ER) is released into the cytoplasm under activated conditions. The resulting emptying of calcium stored in the ER further triggered an extracellular calcium influx into the cells 33 . As shown in Table 1 and Figure 7A, a significant high peak of [Ca 2+ ] i was induced by fMLF in human neutrophils.…”

Section: Resultsmentioning

confidence: 91%

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation

et al. 2020

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Human neutrophils have a vital role in host defense and inflammatory responses in innate immune systems. Growing evidence shows that the overproduction of reactive oxygen species and granular proteolytic enzymes from activated neutrophils is linked to the pathogenesis of acute inflammatory diseases. However, adequate therapeutic targets are still lacking to regulate neutrophil functions. Herein, we report that MVBR-28, synthesized from the Mannich bases of heterocyclic chalcone, has antineutrophilic inflammatory effects through regulation of intracellular pH. MVBR-28 modulates neutrophil functions by attenuating respiratory burst, degranulation, and migration. Conversely, MVBR-28 has no antioxidant effects and fails to alter elastase activity in cell-free systems. The anti-inflammatory effects of MVBR-28 are not seen through cAMP pathways. Significantly, MVBR-28 potently inhibits extracellular Ca 2+ influx in N-formyl-methionyl-leucyl-phenylalanine (fMLF)-and thapsigarginactivated human neutrophils. Notably, MVBR-28 attenuates fMLF-induced intracellular alkalization in a K + -dependent manner, which is upstream of Ca 2+ pathways. |

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Section: Resultsmentioning

confidence: 91%

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation

et al. 2020

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“…Conspicuous absence of the NLRP3 pathway was a notable finding from the DML enrichment analysis. The results suggest a model whereby the DNA methylome can regulate acute and chronic gouty inflammation through signal transduction pathways and transcriptional pathways, including those for leukocyte differentiation and function and for neuroinflammation . The gout DNA methylome potentially acts on immune, metabolic, and other elements that regulate first‐signal NLRP3 inflammasome priming, leading to regulation of phagocyte behavior following second‐signal inflammasome activation by phagocytosed urate crystals .…”

Section: Discussionmentioning

confidence: 93%

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout

Wang

Zhao

Phipps‐Green

et al. 2020

Arthritis & Rheumatology

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Objective. In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout.Methods. Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Māori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed.Results. Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts.Conclusion. These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.

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“…During an active infection, neutrophils migrate to the site of inflammation following chemotactic gradients of chemokines and pathogen-associated molecular patterns (PAMPs) (4,5). Neutrophils eliminate pathogens through phagocytosis, granule release or the production of neutrophil extracellular traps (NETs) (1,6), these mechanisms are in part regulated by mobilization of calcium (Ca 2+ ) and the subsequent Ca 2+ signaling events (7,8).…”

Section: Introductionmentioning

confidence: 99%

The TRPM2 Ion Channel Regulates Inflammatory Functions of Neutrophils During Listeria monocytogenes Infection

et al. 2020

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During infection, phagocytic cells pursue homeostasis in the host via multiple mechanisms that control microbial invasion. Neutrophils respond to infection by exerting a variety of cellular processes, including chemotaxis, activation, phagocytosis, degranulation and the generation of reactive oxygen species (ROS). Calcium (Ca 2+ ) signaling and the activation of specific Ca 2+ channels are required for most antimicrobial effector functions of neutrophils. The transient receptor potential melastatin-2 (TRPM2) cation channel has been proposed to play important roles in modulating Ca 2+ mobilization and oxidative stress in neutrophils. In the present study, we use a mouse model of Listeria monocytogenes infection to define the role of TRPM2 in the regulation of neutrophils' functions during infection. We show that the susceptibility of Trpm2 −/− mice to L. monocytogenes infection is characterized by increased migration rates of neutrophils and monocytes to the liver and spleen in the first 24 h. During the acute phase of L. monocytogenes infection, Trpm2 −/− mice developed septic shock, characterized by increased serum levels of TNF-α, IL-6, and IL-10. Furthermore, in vivo depletion of neutrophils demonstrated a critical role of these immune cells in regulating acute inflammation in Trpm2 −/− infected mice. Gene expression and inflammatory cytokine analyses of infected tissues further confirmed the hyperinflammatory profile of Trpm2 −/− neutrophils. Finally, the increased inflammatory properties of Trpm2 −/− neutrophils correlated with the dysregulated cytoplasmic concentration of Ca 2+ and potentiated membrane depolarization, in response to L. monocytogenes. In conclusion, our findings suggest that the TRPM2 channel plays critical functional roles in regulating the inflammatory properties of neutrophils and preventing tissue damage during Listeria infection.

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Calcium signalling and related ion channels in neutrophil recruitment and function

Cited by 116 publications

References 99 publications

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout

The TRPM2 Ion Channel Regulates Inflammatory Functions of Neutrophils During Listeria monocytogenes Infection

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Calcium signalling and related ion channels in neutrophil recruitment and function

Cited by 116 publications

References 99 publications

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K+‐dependent pH regulation

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K+‐dependent pH regulation

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout

The TRPM2 Ion Channel Regulates Inflammatory Functions of Neutrophils During Listeria monocytogenes Infection

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A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K⁺‐dependent pH regulation