The BK Channel Limits the Pro-Inflammatory Activity of Macrophages
Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the K<sub>Ca</sub>1.1 or BK channel, in regulating neur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/4/322 |
| _version_ | 1797298627902701568 |
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| author | Yihe Chen Nikita Markov Lea Gigon Aref Hosseini Shida Yousefi Darko Stojkov Hans-Uwe Simon |
| author_facet | Yihe Chen Nikita Markov Lea Gigon Aref Hosseini Shida Yousefi Darko Stojkov Hans-Uwe Simon |
| author_sort | Yihe Chen |
| collection | DOAJ |
| description | Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the K<sub>Ca</sub>1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions. |
| first_indexed | 2024-03-07T22:37:47Z |
| format | Article |
| id | doaj.art-8ba83f82ee23434fbf39fae61945088b |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-07T22:37:47Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8ba83f82ee23434fbf39fae61945088b2024-02-23T15:11:43ZengMDPI AGCells2073-44092024-02-0113432210.3390/cells13040322The BK Channel Limits the Pro-Inflammatory Activity of MacrophagesYihe Chen0Nikita Markov1Lea Gigon2Aref Hosseini3Shida Yousefi4Darko Stojkov5Hans-Uwe Simon6Institute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandInstitute of Pharmacology, University of Bern, 3010 Bern, SwitzerlandMacrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the K<sub>Ca</sub>1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions.https://www.mdpi.com/2073-4409/13/4/322AIM2 inflammasomeBK channelcalcium influxmacrophage polarizationpro-inflammatory cytokinekinase |
| spellingShingle | Yihe Chen Nikita Markov Lea Gigon Aref Hosseini Shida Yousefi Darko Stojkov Hans-Uwe Simon The BK Channel Limits the Pro-Inflammatory Activity of Macrophages Cells AIM2 inflammasome BK channel calcium influx macrophage polarization pro-inflammatory cytokine kinase |
| title | The BK Channel Limits the Pro-Inflammatory Activity of Macrophages |
| title_full | The BK Channel Limits the Pro-Inflammatory Activity of Macrophages |
| title_fullStr | The BK Channel Limits the Pro-Inflammatory Activity of Macrophages |
| title_full_unstemmed | The BK Channel Limits the Pro-Inflammatory Activity of Macrophages |
| title_short | The BK Channel Limits the Pro-Inflammatory Activity of Macrophages |
| title_sort | bk channel limits the pro inflammatory activity of macrophages |
| topic | AIM2 inflammasome BK channel calcium influx macrophage polarization pro-inflammatory cytokine kinase |
| url | https://www.mdpi.com/2073-4409/13/4/322 |
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