CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients

Grundy, Seamus; Kaur, Maninder; Plumb, Jonathan; Reynolds, Sarah J.; Hall, Simon R.; House, David; Begg, Malcolm; Ray, David; Singh, Dave

doi:10.1042/cs20130152

Cited by 13 publications

(14 citation statements)

References 32 publications

(41 reference statements)

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“…Exposure to Synta (10 μM) for 1.5 h did not induce any significant cytotoxicity compared to non-treated cells (data are not shown). Similarly, the cytotoxicity of Synta was previously assessed in CD8 cells and it was found that exposure to Synta (up to 10 μM) for 1 h did not result in increased cytotoxicity [33]. Taken together, these results suggest the important role of calcium in response to AgNP-mediated degranulation of mast cells…”

Section: Resultssupporting

confidence: 67%

Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor

2016

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Engineered nanomaterial (ENM)-mediated toxicity often involves triggering immune responses. Mast cells can regulate both innate and adaptive immune responses and are key effectors in allergic diseases and inflammation. Silver nanoparticles (AgNPs) are one of the most prevalent nanomaterials used in consumer products due to their antimicrobial properties. We have previously shown that AgNPs induce mast cell degranulation that was dependent on nanoparticle physicochemical properties. Furthermore, we identified a role for scavenger receptor B1 (SR-B1) in AgNP-mediated mast cell degranulation. However, it is completely unknown how SR-B1 mediates mast cell degranulation and the intracellular signaling pathways involved. In the current study, we hypothesized that SR-B1 interaction with AgNPs directs mast cell degranulation through activation of signal transduction pathways that culminate in an increase in intracellular calcium signal leading to mast cell degranulation. For these studies, we utilized bone marrow-derived mast cells (BMMC) isolated from C57Bl/6 mice and RBL-2H3 cells (rat basophilic leukemia cell line). Our data support our hypothesis and show that AgNP-directed mast cell degranulation involves activation of PI3K, PLCγ and an increase in intracellular calcium levels. Moreover, we found that influx of extracellular calcium is required for the cells to degranulate in response to AgNP exposure and is mediated at least partially via the CRAC channels. Taken together, our results provide new insights into AgNP-induced mast cell activation that are key for designing novel ENMs that are devoid of immune system activation.

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Section: Resultssupporting

confidence: 67%

Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor

2016

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“…The anti-inflammatory effects of dexamethasone were similar in COPD patients and controls, both in PBMCs and CD8 cells from the blood and lung tissue. We have previously reported similar corticosteroid sensitivity in COPD and control CD8 cells from blood and lung tissue [ 15 ]. In contrast, stimulated bronchoalveolar lavage lymphocytes, containing CD4 and CD8 cells, show decreased corticosteroid sensitivity in COPD patients compared to controls [ 26 ].…”

Section: Discussionmentioning

confidence: 82%

“…Pulmonary CD8 cells were isolated as previously described [ 15 ]. Briefly, lung tissue was homogenised in a blender.…”

Section: Methodsmentioning

confidence: 99%

Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells

Grundy¹,

Plumb²,

Kaur³

et al. 2016

Respir Res

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BackgroundCD8 lymphocytes play an important role in the pathogenesis of COPD. Corticosteroids and phosphodiesterase 4 (PDE4) inhibitors are anti-inflammatory drugs used for COPD treatment. Little is known of the combined effect of these drugs on COPD CD8 cells. We studied the effect of corticosteroid combined with PDE4 inhibitors on cytokine release form circulating and pulmonary CD8 cells, and on glucocorticoid (GR) nuclear translocation.MethodsThe effect of dexamethasone alone and in combination with the PDE4 inhibitors roflumilast and GSK256066 on cytokine release from circulating and pulmonary CD8 cells was measured. The effect of the compounds on nuclear translocation of GR and cyclic AMP-responsive element-binding protein (CREB) was studied using immunofluorescence.ResultsDexamethasone inhibited cytokine release from COPD CD8 cells in a concentration dependent manner. PDE4 inhibitors enhanced this anti-inflammatory effect in an additive manner. PDE4 inhibitors did not increase corticosteroid induced GR nuclear translocation. PDE4 inhibitors, but not corticosteroid, increased phospho-CREB nuclear translocation.ConclusionThe combination of corticosteroids and PDE4 inhibitors results in an additive anti-inflammatory effect in COPD CD8 cells. This enhanced anti-inflammatory effect could translate to important clinical benefits for patients with COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0325-8) contains supplementary material, which is available to authorized users.

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“…All compounds were effective in inhibiting both the proliferation (355) and the production of a wide range of cytokines, including IL-2, IFN-γ, TNF-α, and IL-17, by primary human T cells isolated from healthy controls (355) or from diseased tissues such as colonic lamina propria of patients with IBD (353) and lung of patients with chronic obstructive pulmonary disease (356). These findings are consistent with impaired cytokine expression in T cells from ORAI1/STIM1-deficient patients and mice (33, 125–127, 155, 164, 168).…”

Section: Ion Channels As Drug Targets For Immunotherapymentioning

confidence: 99%

Ion Channels in Innate and Adaptive Immunity

Feske¹,

Wulff

Skolnik

2015

Annu. Rev. Immunol.

569

616

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Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

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CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients

Abstract: Background-There are increased numbers of pulmonary CD8 lymphocytes in COPD. Calcium-release activation calcium (CRAC) channels play a central role in lymphocyte activation though the regulation of the transcription factor nuclear factor of activated T cells (NFAT).

Cited by 13 publications

References 32 publications

Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor

Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor

Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells

Ion Channels in Innate and Adaptive Immunity

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