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Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification.
- Source :
-
The FEBS journal [FEBS J] 2021 May; Vol. 288 (10), pp. 3186-3196. Date of Electronic Publication: 2020 Nov 21. - Publication Year :
- 2021
-
Abstract
- The release of interleukin (IL)-1β from primary human monocytes in response to extracellular LPS occurs through the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. In primary monocytes, in response to LPS, NLRP3 inflammasome activation is characterized by an independence of K <superscript>+</superscript> efflux and ASC speck formation and has been termed the 'alternative' pathway. Here, we report that pharmacological inhibition of V-ATPase with bafilomycin A1 exacerbated LPS-induced NLRP3 inflammasome activation in primary human monocytes. Inhibition of V-ATPase in the presence of extracellular LPS led to NLRP3-dependent, K <superscript>+</superscript> efflux-independent, ASC oligomerization and caspase-1 activation. Although V-ATPases are required for lysosomal acidification, we found that acidic lysosomal pH and protease activity were dispensable for this altered response, suggesting that V-ATPase inhibition triggered alternative signalling events. Therefore, V-ATPases may serve additional roles during NLRP3 inflammasome activation in primary human monocytes.<br /> (© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Subjects :
- Caspase 1 genetics
Caspase 1 immunology
Enzyme Inhibitors pharmacology
Gene Expression Regulation
Humans
Hydrogen-Ion Concentration
Inflammasomes immunology
Inflammasomes metabolism
Inflammation
Interleukin-1beta genetics
Interleukin-1beta immunology
Lipopolysaccharides pharmacology
Lysosomes immunology
Lysosomes metabolism
Monocytes cytology
Monocytes immunology
NLR Family, Pyrin Domain-Containing 3 Protein agonists
NLR Family, Pyrin Domain-Containing 3 Protein deficiency
NLR Family, Pyrin Domain-Containing 3 Protein immunology
Nigericin pharmacology
Primary Cell Culture
Proton-Translocating ATPases antagonists & inhibitors
Proton-Translocating ATPases immunology
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases immunology
Signal Transduction
THP-1 Cells
Inflammasomes drug effects
Lysosomes drug effects
Macrolides pharmacology
Monocytes drug effects
NLR Family, Pyrin Domain-Containing 3 Protein genetics
Proton-Translocating ATPases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1742-4658
- Volume :
- 288
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 33145969
- Full Text :
- https://doi.org/10.1111/febs.15619