Aquaporin-3 is involved in NLRP3-inflammasome activation contributing to the setting of inflammatory response
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Aquaporin‑3 is involved in NLRP3‑inflammasome activation contributing to the setting of inflammatory response Inês Vieira da Silva1,2 · Carlos Cardoso2,3 · Helios Martínez‑Banaclocha4 · Angela Casini5 · Pablo Pelegrín4 · Graça Soveral1,2 Received: 17 December 2019 / Revised: 23 October 2020 / Accepted: 11 November 2020 © Springer Nature Switzerland AG 2020
Abstract Inflammasomes are large immune multiprotein complexes that tightly regulate the production of the pro-inflammatory cytokines, being dependent on cell regulatory volume mechanisms. Aquaporins (AQPs) are protein channels that facilitate the transport of water and glycerol (aquaglyceroporins) through membranes, essential for cell volume regulation. Although these membrane proteins are highly expressed in monocytes and macrophages, their role in the inflammatory process is still unclear. Here, we investigated the role of aquaglyceroporin AQP3 in NLRP3-inflammasome activation by complementary approaches based either on shRNA silencing or on AQP3 selective inhibition. The latter has been achieved using a reported potent gold-based inhibitor, Auphen. AQP3 inhibition or silencing partially blocked LPS-priming and decreased production of IL-6, proIL-1β, and TNF-α, suggesting the possible involvement of AQP3 in macrophage priming by Toll-like receptor 4 engagement. Moreover, AQP3-dependent cell reswelling increased IL-1β release through caspase-1 activation. NLRP3inflammasome activation induced by reswelling, nigericin, and ATP was also blocked when AQP3 was inhibited or silenced. Altogether, these data point towards AQPs as potential players in the setting of the inflammatory response. Keywords Aquaglyceroporin · Inflammasome · Inflammation · Interleukin-1 · Macrophages · Water and glycerol permeability
Pablo Pelegrín and Graça Soveral joint senior authors. * Pablo Pelegrín [email protected] * Graça Soveral [email protected] 1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649‑003 Lisboa, Portugal
2
Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649‑003 Lisboa, Portugal
3
Clinical Chemistry Laboratory, Dr. Joaquim Chaves, 1495‑148 Algés, Portugal
4
Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de La Arrixaca, Carretera Buenavista, 30120 Murcia, Spain
5
Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748 Garching b. München, Germany
Abbreviations AQP Aquaporin ATP Adenosine triphosphate Casp-1 Caspase-1 GSDMD Gasdermin D IL Interleukin NF-κB Nuclear factor-κB NLRP3 Nucleotide-binding oligomerization domainlike receptors family pyrin domain containing 3 Pf Osmotic water permeability Pgly Glycerol permeability TNF-α Tumor necrosis factor alpha
Introduction Inflammasomes are large immune multiprotein complexes that tightly regulate the production
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