PMID- 38391935
OWN - NLM
STAT- MEDLINE
DCOM- 20240226
LR  - 20240226
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 13
IP  - 4
DP  - 2024 Feb 9
TI  - The BK Channel Limits the Pro-Inflammatory Activity of Macrophages.
LID - 10.3390/cells13040322 [doi]
LID - 322
AB  - 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(Ca)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(2+)/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-1beta 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-1beta 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.
FAU - Chen, Yihe
AU  - Chen Y
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Markov, Nikita
AU  - Markov N
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Gigon, Lea
AU  - Gigon L
AUID- ORCID: 0000-0002-1142-7283
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Hosseini, Aref
AU  - Hosseini A
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Yousefi, Shida
AU  - Yousefi S
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Stojkov, Darko
AU  - Stojkov D
AUID- ORCID: 0000-0001-9243-3759
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
FAU - Simon, Hans-Uwe
AU  - Simon HU
AUID- ORCID: 0000-0002-9404-7736
AD  - Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
AD  - Institute of Biochemistry, Brandenburg Medical School, 16816 Neuruppin, Germany.
LA  - eng
GR  - 310030_184816/SNSF_/Swiss National Science Foundation/Switzerland
PT  - Journal Article
DEP - 20240209
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Inflammasomes)
RN  - 0 (Large-Conductance Calcium-Activated Potassium Channels)
RN  - SY7Q814VUP (Calcium)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
SB  - IM
MH  - *Inflammasomes/metabolism
MH  - *Large-Conductance Calcium-Activated Potassium Channels/metabolism
MH  - Calcium/metabolism
MH  - Macrophages/metabolism
MH  - Immunity, Innate
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
PMC - PMC10886595
OTO - NOTNLM
OT  - AIM2 inflammasome
OT  - BK channel
OT  - calcium influx
OT  - kinase
OT  - macrophage polarization
OT  - pro-inflammatory cytokine
COIS- The authors declare no conflicts of interest. The funders had no role in the 
      design of the study, in the collection, analyses, or interpretation of data, in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2024/02/23 12:44
MHDA- 2024/02/26 06:45
PMCR- 2024/02/09
CRDT- 2024/02/23 10:16
PHST- 2024/01/07 00:00 [received]
PHST- 2024/01/31 00:00 [revised]
PHST- 2024/02/07 00:00 [accepted]
PHST- 2024/02/26 06:45 [medline]
PHST- 2024/02/23 12:44 [pubmed]
PHST- 2024/02/23 10:16 [entrez]
PHST- 2024/02/09 00:00 [pmc-release]
AID - cells13040322 [pii]
AID - cells-13-00322 [pii]
AID - 10.3390/cells13040322 [doi]
PST - epublish
SO  - Cells. 2024 Feb 9;13(4):322. doi: 10.3390/cells13040322.