Calcium-Activated Potassium Channel KCa3.1 in Lung Dendritic Cell Migration

Shao, Zhifei; Makinde, Toluwalope O.; Agrawal, Devendra K.

doi:10.1165/rcmb.2010-0514oc

Cited by 28 publications

(24 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from the involvement of CCR7 and CCR8 chemokine receptors in the migration of antigen-carrying lung DCs to draining lymph nodes [89], we have recently found that calcium-activated potassium channel, KCa3.1, is a key player in regulating the chemotaxis of DCs in the lungs [92]. Migration of DC via KCa3.1 is modulated at two levels where by CCR7 activation is modulated by the activation state of KCa3.1 via CCL19/CCL21-dependent intracellular calcium release.…”

Section: Chemotaxis Of Dcsmentioning

confidence: 99%

“…Higher expression of CCR7 assists in the activation of KCa3.1. Furthermore, higher expression levels of KCa3.1 in lung DCs under atopic conditions necessitate its involvement in DC migration [92]. Further understanding on the molecular and chemical signals to attract different DC subsets could help us devise better therapies for allergic airway inflammatory conditions..…”

Section: Chemotaxis Of Dcsmentioning

confidence: 99%

See 1 more Smart Citation

Clinical view on the importance of dendritic cells in asthma

Gaurav

Agrawal

2013

Expert Review of Clinical Immunology

View full text Add to dashboard Cite

Summary Allergic asthma is characterized by airway hyperresponsiveness and inflammation and may lead to airway remodeling in uncontrolled cases. Genetic predisposition to an atopic phenotype plays a major component in the pathophysiology of asthma. However, with tremendous role of epigenetic factors and environmental stimuli in precipitating an immune response, the underlying pathophysiological mechanisms are complicated. Dendritic cells are principal antigen presenting cells and initiators of the immune response in allergic asthma. Their phenotype, guided by multiple factors may dictate the immune reaction to an allergic or tolerogenic response. Involvement of the local cytokine milieu, microbiome and interplay between immune cells add dimension to the fate of immune response. In addition to allergen exposure, these factors modulate DC phenotype and function. In this article, integration of many factors and pathways associated with the recruitment and activation of DCs in the pathophysiology of allergic asthma is presented in a clinical and translational manner.

show abstract

Section: Chemotaxis Of Dcsmentioning

confidence: 99%

Section: Chemotaxis Of Dcsmentioning

confidence: 99%

Clinical view on the importance of dendritic cells in asthma

Gaurav

Agrawal

2013

Expert Review of Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…The underlying mechanisms by which K Ca 3.1 channels contribute to the pathogenesis of allergic asthma are yet to be defined but we have shown that K Ca 3.1 channels regulate mast cell degranulation and migration (26–29), and fibrocyte migration (30). Others have implicated K Ca 3.1 channels in the migration of lung dendritic cells to CCL19 and CCL21 (31). These observations demonstrate that activation of K Ca 3.1 channels on structural (smooth muscle/fibroblasts) airway cells may represent an important pathway driving key features of allergic asthma.…”

Section: Introductionmentioning

confidence: 99%

Functional KCa3.1 Channels Regulate Steroid Insensitivity in Bronchial Smooth Muscle Cells

Chachi

Shikotra

Duffy

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Identifying the factors responsible for relative glucocorticosteroid (GC) resistance present in patients with severe asthma and finding tools to reverse it are of paramount importance. In asthma there is in vivo evidence of GC-resistant pathways in airway smooth muscle (ASM) bundles which can be modelled in vitro by exposing cultured ASM cells to TNFα/IFNγ. This drives GC insensitivity via protein phosphatase-5 (PP5)-dependent impairment of GC receptor (GR) phosphorylation. Here, we investigated whether KCa3.1 ion channels modulate the activity of GC-resistant pathways using our ASM model of GC insensitivity. Immunohistochemical staining of endobronchial biopsies revealed that KCa3.1 channels are localized to the plasma membrane and nucleus of ASM in both healthy controls and asthmatic patients, irrespective of disease severity. Western blot assays and immunofluorescence staining confirmed the nuclear localisation of KCa3.1 channels in ASM cells. The functional importance of KCa3.1 channels in the regulation of GC-resistant chemokines induced by TNFα/IFNγ was assessed using complementary inhibitory strategies including KCa3.1 blockers (TRAM-34 and ICA-17043) or KCa3.1-specific shRNA delivered by adenoviruses. KCa3.1 channel blockade led to a significant reduction of fluticasone-resistant CX3CL1, CCL5 and CCL11 gene and protein expression. KCa3.1 channel blockade also restored fluticasone-induced GRα phosphorylation at ser211 and transactivation properties via the suppression of cytokine-induced PP5 expression. The effect of KCa3.1 blockade was evident in ASM cells from both healthy controls and asthmatic subjects. In summary KCa3.1 channels contribute to the regulation of GC-resistant inflammatory pathways in ASM cells: blocking KCa3.1 channels may enhance corticosteroid activity in severe asthma.

show abstract

“…We have recently reported that intermediate conductance calcium-activated potassium channel, KCa3.1, is expressed in immunogenic and regulatory mouse lung DCs [25, 26] and is actively involved in DC migration to lymphatic chemokines by modulating CCL19/CCL21-induced Ca 2+ influx [27]. In fact, KCa3.1 is expressed in almost all types of immune cells, including T cell [28], macrophage [29] and mast cells [30], and plays a key role in calcium-dependent cell activities such as migration [30-33], particularly under pathological conditions when calcium signaling is highly active.…”

Section: Introductionmentioning

confidence: 99%

Intermediate-conductance calcium-activated potassium channel KCa3.1 and chloride channel modulate chemokine ligand (CCL19/CCL21)-induced migration of dendritic cells

Shao

Gaurav

Agrawal

2015

Translational Research

Self Cite

View full text Add to dashboard Cite

The role of ion channels is largely unknown in chemokine-induced migration in non-excitable cells such as dendritic cells. Here, we examined the role of KCa3.1 and chloride channels in lymphatic chemokines-induced migration of dendritic cells. The amplitude and kinetics of CCL19/21-induced Ca2+ influx were associated with CCR7 expression levels, extracellular free Ca2+ and Cl−, and independent of extracellular K+. Chemokines, CCL19 and CCL21, and KCa3.1 activator, 1-EBIO, induced plasma membrane hyperpolarization and K+ efflux, which was blocked by TRAM-34, suggesting that KCa3.1 carried larger conductance than the inward CRAC. Blockade of KCa3.1, low Cl− in the medium, and low dose of DIDS impaired CCL19/CCL21-induced Ca2+ influx, cell volume change, and DC migration. High doses of DIDS completely blocked DC migration possibly by significantly disrupting mitochondrial membrane potential. In conclusion, KCa3.1 and chloride channel are critical in human DC migration by synergistically regulating membrane potential, chemokine-induced Ca2+ influx, and cell volume.

show abstract

Calcium-Activated Potassium Channel KCa3.1 in Lung Dendritic Cell Migration

Cited by 28 publications

References 36 publications

Clinical view on the importance of dendritic cells in asthma

Clinical view on the importance of dendritic cells in asthma

Functional KCa3.1 Channels Regulate Steroid Insensitivity in Bronchial Smooth Muscle Cells

Intermediate-conductance calcium-activated potassium channel KCa3.1 and chloride channel modulate chemokine ligand (CCL19/CCL21)-induced migration of dendritic cells

Contact Info

Product

Resources

About