PMID- 36798132
OWN - NLM
STAT- MEDLINE
DCOM- 20230222
LR  - 20230307
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 14
DP  - 2023
TI  - Inhibition of sphingosine-1-phosphate receptor 3 suppresses ATP-induced NLRP3 
      inflammasome activation in macrophages via TWIK2-mediated potassium efflux.
PG  - 1090202
LID - 10.3389/fimmu.2023.1090202 [doi]
LID - 1090202
AB  - BACKGROUND: Inhibition of sphingosine kinase 1 (SphK1), which catalyzes bioactive 
      lipid sphingosine-1-phosphate (S1P), attenuates NLRP3 inflammasome activation. 
      S1P exerts most of its function by binding to S1P receptors (S1PR1-5). The roles 
      of S1P receptors in NLRP3 inflammasome activation remain unclear. MATERIALS AND 
      METHODS: The mRNA expressions of S1PRs in bone marrow-derived macrophages (BMDMs) 
      were measured by real-time quantitative polymerase chain reaction (qPCR) assays. 
      BMDMs were primed with LPS and stimulated with NLRP3 activators, including ATP, 
      nigericin, and imiquimod. Interleukin-1beta (IL-1beta) in the cell culture supernatant 
      was detected by enzyme-linked immunosorbent assay (ELISA). Intracellular 
      potassium was labeled with a potassium indicator and was measured by confocal 
      microscopy. Protein expression in whole-cell or plasma membrane fraction was 
      measured by Western blot. Cecal ligation and puncture (CLP) was induced in 
      C57BL/6J mice. Mortality, lung wet/dry ratio, NLRP3 activation, and bacterial 
      loads were measured. RESULTS: Macrophages expressed all five S1PRs in the resting 
      state. The mRNA expression of S1PR3 was upregulated after lipopolysaccharide 
      (LPS) stimulation. Inhibition of S1PR3 suppressed NLRP3 and pro-IL-1beta in 
      macrophages primed with LPS. Inhibition of S1PR3 attenuated ATP-induced NLRP3 
      inflammasome activation, enhanced nigericin-induced NLRP3 activation, and did not 
      affect imiquimod-induced NLRP3 inflammasome activation. In addition, inhibition 
      of S1PR3 suppressed ATP-induced intracellular potassium efflux. Inhibition of 
      S1PR3 did not affect the mRNA or protein expression of TWIK2 in LPS-primed BMDMs. 
      ATP stimulation induced TWIK2 expression in the plasma membrane of LPS-primed 
      BMDMs, and inhibition of S1PR3 impeded the membrane expression of TWIK2 induced 
      by ATP. Compared with CLP mice treated with vehicle, CLP mice treated with the 
      S1PR3 antagonist, TY52156, had aggravated pulmonary edema, increased bacterial 
      loads in the lung, liver, spleen, and blood, and a higher seven-day mortality 
      rate. CONCLUSIONS: Inhibition of S1PR3 suppresses the expression of NLRP3 and 
      pro-IL-1beta during LPS priming, and attenuates ATP-induced NLRP3 inflammasome 
      activation by impeding membrane trafficking of TWIK2 and potassium efflux. 
      Although inhibition of S1PR3 decreases IL-1beta maturation in the lungs, it leads to 
      higher bacterial loads and mortality in CLP mice.
CI  - Copyright (c) 2023 Wang, Wang, He, Chen, Yu, Cang and Zhong.
FAU - Wang, Yingqin
AU  - Wang Y
AD  - Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Wang, Chen
AU  - Wang C
AD  - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 
      Shanghai, China.
FAU - He, Qiaolan
AU  - He Q
AD  - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 
      Shanghai, China.
FAU - Chen, Guannan
AU  - Chen G
AD  - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 
      Shanghai, China.
FAU - Yu, Jie
AU  - Yu J
AD  - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 
      Shanghai, China.
FAU - Cang, Jing
AU  - Cang J
AD  - Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 
      China.
FAU - Zhong, Ming
AU  - Zhong M
AD  - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 
      Shanghai, China.
AD  - Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China.
AD  - Shanghai Institute of Infectious Disease and Biosecurity, School of Public 
      Health, Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230131
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Sphingosine-1-Phosphate Receptors)
RN  - RWP5GA015D (Potassium)
RN  - P1QW714R7M (Imiquimod)
RN  - RRU6GY95IS (Nigericin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 0 (RNA, Messenger)
RN  - 0 (Nlrp3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Inflammasomes/metabolism
MH  - *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Lipopolysaccharides/pharmacology/metabolism
MH  - Sphingosine-1-Phosphate Receptors/metabolism
MH  - Potassium/metabolism
MH  - Imiquimod
MH  - Nigericin/pharmacology
MH  - Mice, Inbred C57BL
MH  - Macrophages/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - RNA, Messenger/metabolism
PMC - PMC9927198
OTO - NOTNLM
OT  - NLRP3 inflammasome
OT  - TWIK2
OT  - macrophage
OT  - sepsis
OT  - sphingosine-1-phosphate receptor
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/02/18 06:00
MHDA- 2023/02/22 06:00
PMCR- 2023/01/01
CRDT- 2023/02/17 02:04
PHST- 2022/11/05 00:00 [received]
PHST- 2023/01/16 00:00 [accepted]
PHST- 2023/02/17 02:04 [entrez]
PHST- 2023/02/18 06:00 [pubmed]
PHST- 2023/02/22 06:00 [medline]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2023.1090202 [doi]
PST - epublish
SO  - Front Immunol. 2023 Jan 31;14:1090202. doi: 10.3389/fimmu.2023.1090202. 
      eCollection 2023.