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In primary monocytes, in response to LPS, NLRP3 inflammasome activation is characterized by an independence of K<jats:sup>+<\/jats:sup> efflux and ASC speck formation and has been termed the \u2018alternative\u2019 pathway. Here, we report that pharmacological inhibition of V\u2010ATPase with bafilomycin A1 exacerbated LPS\u2010induced NLRP3 inflammasome activation in primary human monocytes. Inhibition of V\u2010ATPase in the presence of extracellular LPS led to NLRP3\u2010dependent, K<jats:sup>+<\/jats:sup> efflux\u2010independent, ASC oligomerization and caspase\u20101 activation. Although V\u2010ATPases are required for lysosomal acidification, we found that acidic lysosomal pH and protease activity were dispensable for this altered response, suggesting that V\u2010ATPase inhibition triggered alternative signalling events. Therefore, V\u2010ATPases may serve additional roles during NLRP3 inflammasome activation in primary human monocytes.<\/jats:p>","DOI":"10.1111\/febs.15619","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T09:06:36Z","timestamp":1604480796000},"page":"3186-3196","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification"],"prefix":"10.1111","volume":"288","author":[{"given":"Shi","family":"Yu","sequence":"first","affiliation":[{"name":"Division of Neuroscience and Experimental Psychology School of Biological Sciences Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre University of Manchester UK"},{"name":"Lydia Becker Institute of Immunology and Inflammation University of Manchester 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