Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification
| Autor: | David Brough, Rose Wellens, Shi Yu, Jack Peter Green, Gloria Lopez-Castejon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Inflammasomes THP-1 Cells medicine.medical_treatment Interleukin-1beta Biochemistry Monocytes immunology chemistry.chemical_compound 0302 clinical medicine caspase 1 cytokine Enzyme Inhibitors integumentary system Bafilomycin Interleukin Inflammasome Hydrogen-Ion Concentration Cell biology Proton-Translocating ATPases alternative NLRP3 inflammasome medicine.anatomical_structure Cytokine 030220 oncology & carcinogenesis Receptor-Interacting Protein Serine-Threonine Kinases monocyte Original Article Macrolides medicine.symptom medicine.drug Signal Transduction Primary Cell Culture Caspase 1 Inflammation interleukin 1 03 medical and health sciences NLRP3 inflammasome NLR Family Pyrin Domain-Containing 3 Protein medicine Extracellular Humans Molecular Biology Monocyte Cell Biology Original Articles 030104 developmental biology chemistry Gene Expression Regulation Nigericin immune cell Lysosomes |
| Zdroj: | Yu Shi, A, Green, J, Wellens, R, Lopez-Castejon, G & Brough, D 2020, ' Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification ', The FEBS Journal . https://doi.org/10.1111/febs.15619 The Febs Journal |
| DOI: | 10.1111/febs.15619 |
| Popis: | The NLRP3 inflammasome drives inflammation in response to tissue damage and infection by promoting the processing and release of IL‐1β. Human monocytes have an alternative pathway of NLRP3 inflammasome activation in response to lipopolysaccharide alone. Here, we report that the vacuolar ATPase, a lysosomal proton pump, is a regulator of the alternative NLRP3 response. 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+ 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+ 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. |
| Databáze: | OpenAIRE |
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