Regulatory role of KCa3.1 in immune cell function and its emerging association with rheumatoid arthritis

Lin, Yi; Zhao, Yingjie; Zhang, Hailin; Hao, Wen‐Juan; Zhu, Ren-Di; Wang, Yan; Hu, Wei; Zhou, Renpeng

doi:10.3389/fimmu.2022.997621

Cited by 8 publications

(7 citation statements)

References 141 publications

(165 reference statements)

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“…The increased number of autoreactive B cells plays an important role in the activation of autoreactive T cells ( Wu et al, 2021a ). KCa3.1 channels are expressed in B cells and regulate the migration and proliferation of B cells ( Lin et al, 2022 ). B cells, as APCs, present their own antigens to CD4 + T helper cells, which results in an increase in the number of follicular helper T cells (Tfh) and peripheral helper T cells (Tph) in the synovium of RA patients ( Lucas et al, 2020 ).…”

Section: Immune System In Ramentioning

confidence: 99%

“…T cells have a significant role in disease perpetuation as they are a source of pro-inflammatory cytokines and interact with synovial stromal cells ( Scherer and Burmester, 2011 ; Komatsu et al, 2014 ). In T cells, the KCa3.1 channels initiate the expression of genes that promote T-cell activation and proliferation ( Lin et al, 2022 ). Lines of evidence suggested that CD4 + T cells and CD8 + T cells play an important role in the progress and pathogenesis of RA ( Jang et al, 2022 ).…”

Section: Immune System In Ramentioning

confidence: 99%

“…Lines of evidence suggested that CD4 + T cells and CD8 + T cells play an important role in the progress and pathogenesis of RA ( Jang et al, 2022 ). KCa3.1 channels support the migration of CD8 + T cells to the site of inflammation ( Lin et al, 2022 ). In most of the cases, infiltration of a large number of CD4 + T cells is observed in the joint synovium and tenosynovium of RA patients, and these CD4 + T cells act as activation markers of T cells ( Kaibara et al, 2008 ).…”

Section: Immune System In Ramentioning

confidence: 99%

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Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

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Mandlik,

Zine

et al. 2024

Front. Pharmacol.

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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the synovial joint, which leads to inflammation, loss of function, joint destruction, and disability. The disease biology of RA involves complex interactions between genetic and environmental factors and is strongly associated with various immune cells, and each of the cell types contributes differently to disease pathogenesis. Several immunomodulatory molecules, such as cytokines, are secreted from the immune cells and intervene in the pathogenesis of RA. In immune cells, membrane proteins such as ion channels and transporters mediate the transport of charged ions to regulate intracellular signaling pathways. Ion channels control the membrane potential and effector functions such as cytotoxic activity. Moreover, clinical studies investigating patients with mutations and alterations in ion channels and transporters revealed their importance in effective immune responses. Recent studies have shown that voltage-gated potassium channels and calcium-activated potassium channels and their subtypes are involved in the regulation of immune cells and RA. Due to the role of these channels in the pathogenesis of RA and from multiple pieces of clinical evidence, they can be considered therapeutic targets for the treatment of RA. Here, we describe the role of voltage-gated and calcium-activated potassium channels and their subtypes in RA and their pharmacological application as drug targets.

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Section: Immune System In Ramentioning

confidence: 99%

Section: Immune System In Ramentioning

confidence: 99%

Section: Immune System In Ramentioning

confidence: 99%

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Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

More,

Mandlik,

Zine

et al. 2024

Front. Pharmacol.

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“…Rheumatoid arthritis (RA) is a chronic rheumatic disease characterized by progressive joint damage and synovial inflammation 1–3 . The global RA prevalence estimate was about 460 per 100 000 population between 1980 and 2019 4 .…”

Section: Introductionmentioning

confidence: 99%

Meta‐analysis reveals that rheumatoid arthritis is associated with worse clinical outcomes among patients with COVID‐19

Zhang,

Liu,

Wang

et al. 2024

Int J of Rheum Dis

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Patients with rheumatoid arthritis (RA) are reported to be more vulnerable to coronavirus disease 2019 (COVID‐19), so clinical severity is a particular concern for them. This meta‐analysis was performed to evaluate the clinical outcomes in RA patients with COVID‐19. A systematic literature search was performed in electronic databases for relevant articles published from January 2020 to October 2022. We extracted necessary relevant data and Egger's test was used to evaluate the risk of publication bias. This meta‐analysis included 9 studies with a total of 12 339 RA patients with COVID‐19 and 685 982 non‐RA patients with COVID‐19. We found serious adverse outcomes in RA patients with COVID‐19, including the rates of severity (OR: 1.59, 95% CI: 1.23–2.05, p = .0004), hospitalization (OR: 1.73, 95% CI: 1.55–1.92, p < .00001), mortality (OR: 1.92, 95% CI: 1.67–2.20, p < .00001), mechanical ventilation (OR: 1.64, 95% CI: 1.47–1.84, p < .00001), despite no significant difference observed in ICU admission (OR: 1.37, 95% CI: 0.95–1.98, p = .09). Our data suggests that RA patients had an increased risk of adverse clinical outcomes with COVID‐19 infection.

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“…There are several molecules that enhance the current through KCa3.1 ( Lin et al, 2022 ). The oldest positive modulator is 1-EBIO ( Devor et al, 1996 ), but several other, stronger activators have thereafter been developed ( Christophersen and Wulff, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

Cozzolino,

Panyi

2024

Front. Pharmacol.

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Background:The unique microenvironment in tumors inhibits the normal functioning of tumor-infiltrating lymphocytes, leading to immune evasion and cancer progression. Over-activation of KCa3.1 using positive modulators has been proposed to rescue the anti-tumor response. One of the key characteristics of the tumor microenvironment is extracellular acidity. Herein, we analyzed how intra- and extracellular pH affects K+ currents through KCa3.1 and if the potency of two of its positive modulators, Riluzole and SKA-31, is pH sensitive.Methods:Whole-cell patch-clamp was used to measure KCa3.1 currents either in activated human peripheral lymphocytes or in CHO cells transiently transfected with either the H192A mutant or wild-type hKCa3.1 in combination with T79D-Calmodulin, or with KCa2.2.Results:We found that changes in the intra- and extracellular pH minimally influenced the KCa3.1-mediated K+ current. Extracellular pH, in the range of 6.0–8.0, does not interfere with the capacity of Riluzole and SKA-31 to robustly activate the K+ currents through KCa3.1. Contrariwise, an acidic intracellular solution causes a slow, but irreversible loss of potency of both the activators. Using different protocols of perfusion and depolarization we demonstrated that the loss of potency is strictly time and pH-dependent and that this peculiar effect can be observed with a structurally similar channel KCa2.2. While two different point mutations of both KCa3.1 (H192A) and its associated protein Calmodulin (T79D) do not limit the effect of acidity, increasing the cytosolic Ca2+ concentration to saturating levels eliminated the loss-of-potency phenotype.Conclusion:Based on our data we conclude that KCa3.1 currents are not sensitive the either the intracellular or the extracellular pH in the physiological and pathophysiological range. However, intracellular acidosis in T cells residing in the tumor microenvironment could hinder the potentiating effect of KCa3.1 positive modulators administered to boost their activity. Further research is warranted both to clarify the molecular interactions between the modulators and KCa3.1 at different intracellular pH conditions and to define whether this loss of potency can be observed in cancer models as well.

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Regulatory role of KCa3.1 in immune cell function and its emerging association with rheumatoid arthritis

Cited by 8 publications

References 141 publications

Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

Meta‐analysis reveals that rheumatoid arthritis is associated with worse clinical outcomes among patients with COVID‐19

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

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