Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine

Schroeder, María Eugenia; Russo, Sofía; Costa, Carlos Henrique Nery; Hori, Juliana Issa; Tiscornia, Inés; Bollati-Fogolín, Mariela; Zamboni, Dario S.; Ferreira, Gonzalo; Cairoli, Ernesto; Hill, Marcelo

doi:10.1038/s41598-017-01836-8

Cited by 43 publications

(31 citation statements)

References 26 publications

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“…We recently showed that Ca 2+ -activated K + channels are involved in ATP-triggered inflammasome activation ( Schroeder et al., 2017 ). We therefore inhibited Ca 2+ -activated K + channels in ATP-treated WT and Tmem176b −/− BMDCs and determined the amounts of IL-1β in culture supernatants.…”

Section: Resultsmentioning

confidence: 99%

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation

et al. 2019

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Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8 + T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1b activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8 + T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.

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Section: Resultsmentioning

confidence: 99%

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation

et al. 2019

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“…Hydroxychloroquine sulfate and chloroquine can block internal TLR signaling and reduce the production of proinflammatory cytokines, and they have been widely used to treat autoimmune diseases like arthritis (73). Hydroxychloroquine can also inhibit proinflammatory Ca 2+ -activated K + channels, leading to impaired inflammasome activation (74). On the other hand, chloroquine has been shown to have significant anti-SARS-CoV-2 efficacy both in vivo and in vitro (75,76).…”

Section: Other Anti-inflammatory Treatmentsmentioning

confidence: 99%

Immunomodulation for Severe COVID-19 Pneumonia: The State of the Art

2020

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“…masome activation in human and mouse macrophage and dendritic cells (25). BK channel blockers were able to suppress myelin phagocytosis of LPS-activated rat macrophages (26) and abrogate the elevations of some inflammatory biomarkers (chemokines and cytokines) in urine specimens of mice whose bladders were inoculated with LPS or uropathogenic E. coli (20).…”

Section: Bk Channel Modulates Neuroinflammationmentioning

confidence: 97%

Large-conductance calcium-activated potassium channels mediate lipopolysaccharide-induced activation of murine microglia

Yang¹,

Wang²,

Cao

et al. 2019

Journal of Biological Chemistry

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Edited by Roger J. Colbran Large-conductance calcium-activated potassium (BK) channels are ubiquitously expressed in most cell types where they regulate many cellular, organ, and organismal functions. Although BK currents have been recorded specifically in activated murine and human microglia, it is not yet clear whether and how the function of this channel is related to microglia activation. Here, using patch-clamping, Griess reaction, ELISA, immunocytochemistry, and immunoblotting approaches, we show that specific inhibition of the BK channel with paxilline (10 M) or siRNA-mediated knockdown of its expression significantly suppresses lipopolysaccharide (LPS)-induced (100 ng/ml) BV-2 and primary mouse microglial cell activation. We found that membrane BK current is activated by LPS at a very early stage through Toll-like receptor 4 (TLR4), leading to nuclear translocation of NF-B and to production of inflammatory cytokines. Furthermore, we noted that BK channels are also expressed intracellularly, and their nuclear expression significantly increases in late stages of LPS-mediated microglia activation, possibly contributing to production of nitric oxide, tumor necrosis factor-␣, and interleukin-6. Of note, a specific TLR4 inhibitor suppressed BK channel expression, whereas an NF-B inhibitor did not. Taken together, our findings indicate that BK channels participate in both the early and the late stages of LPSstimulated murine microglia activation involving both membrane-associated and nuclear BK channels. This work was supported by National Natural Science Foundation of China Grants 31400924 (to X. S.) and 31401197 (to X. T.) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Fig. S1.

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Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine

Cited by 43 publications

References 26 publications

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation

Immunomodulation for Severe COVID-19 Pneumonia: The State of the Art

Large-conductance calcium-activated potassium channels mediate lipopolysaccharide-induced activation of murine microglia

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