Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation
Metabolic regulation is a key feature of inflammasome activation and effector function. Using metabolomic approaches, we show that downregulation of taurine metabolism is crucial for NLRP3 inflammasome activation. Following NLRP3 activation stimuli, taurine rapidly egresses to the extracellular compartment. Taurine efflux is facilitated primarily by the volume-regulated anion channel (VRAC). Loss of intracellular taurine impairs sodium-potassium ATPase pump activity, promoting ionic dysregulation and disrupting ionic fluxes. Inhibiting VRAC, or supplementation of taurine, restores the ionic balance, abrogates IL-1β release, and reduces cellular cytotoxicity in macrophages. We further demonstrate that the protective effect of taurine is diminished when sodium-potassium ATPase is inhibited, highlighting the pump's role in taurine-mediated protection. Finally, taurine metabolism is significantly associated with the development of tuberculosis-associated immune reconstitution inflammatory syndrome, a systemic hyperinflammatory condition known to be mediated by inflammasome activation. Altogether, we identified a critical metabolic pathway that modulates inflammasome activation and drives disease pathogenesis.
Authors
- Rachel Lai (ORCID: https://orcid.org/0000-0003-3418-850X)
- Graeme Meintjes (ORCID: https://orcid.org/0000-0003-1196-4414)
- Jack Green (ORCID: https://orcid.org/0000-0003-1108-3422)
- Shiranee Sriskandan (ORCID: https://orcid.org/0000-0002-5214-4941)
- Alice E. Denton (ORCID: https://orcid.org/0000-0002-4580-3443)
- Juri Kim (ORCID: https://orcid.org/0009-0003-6813-2798)
- Raymond M Moseki (ORCID: https://orcid.org/0000-0002-7792-7977)
- David Thomas (ORCID: https://orcid.org/0000-0002-9738-2329)
- Peter Rossi-Smith
- Robert John Wilkinson (ORCID: https://orcid.org/0000-0002-2753-1800)
- Cecilia Wieder (ORCID: https://orcid.org/0000-0003-1548-4346)
- Paras Anand (ORCID: https://orcid.org/0000-0003-2503-3653)
- Mariana Silva dos Santos (ORCID: https://orcid.org/0000-0003-2404-8490)
- Cari Stek (ORCID: https://orcid.org/0000-0001-8813-0819)
- Antoni Olona
- Trevor J. Ferris (ORCID: https://orcid.org/0000-0002-4179-3831)
- Paige M Mortimer (ORCID: https://orcid.org/0000-0002-8552-2996)
- Timothy M. D. Ebbels (ORCID: https://orcid.org/0000-0002-3372-8423)
- Kristin K. Huse (ORCID: https://orcid.org/0000-0001-8989-1863)
- Nicholas J. Matheson (ORCID: https://orcid.org/0000-0002-3318-1851)
- James I. MacRae (ORCID: https://orcid.org/0000-0002-1464-8583)
- Kamil Skirlo (ORCID: https://orcid.org/0009-0009-5219-2220)
Institutions
- University of Cape Town (ZA)
- University of Cambridge (GB)
- The Francis Crick Institute (GB)
- University of Manchester (GB)
- NIHR Imperial Biomedical Research Centre (GB)
- Wellcome Centre for Infectious Diseases Research in Africa (ZA)
- Imperial College London (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116317
- Citations
- 4
- Primary Topic
- Aldose Reductase and Taurine
- Type
- article
- Field-Weighted Citation Impact
- 4.61