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Nature communications
Sep 18, 2024;15 (1): 8179.

Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation.

Twinu Wilson Chirayath, Matthias Ollivier, Mete Kayatekin, Isabelle Rubera, Chinh Nghia Pham, Jonas Friard, Nathalie Linck, Hélene Hirbec, Christèle Combes, Mylène Zarka, Frédéric Lioté, Pascal Richette, Francois Rassendren, Vincent Compan, Christophe Duranton, Hang Korng Ea
Author Information
  1. Twinu Wilson Chirayath: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France.
  2. Matthias Ollivier: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France.
  3. Mete Kayatekin: Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France.
  4. Isabelle Rubera: Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France. ORCID
  5. Chinh Nghia Pham: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France.
  6. Jonas Friard: Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France.
  7. Nathalie Linck: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France.
  8. Hélene Hirbec: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France. ORCID
  9. Christèle Combes: Université Toulouse, ENSACIET, INPT-CNRS, F-31000, Toulouse, France.
  10. Mylène Zarka: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France.
  11. Frédéric Lioté: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France. ORCID
  12. Pascal Richette: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France. ORCID
  13. Francois Rassendren: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France. ORCID
  14. Vincent Compan: Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France. vincent.compan@igf.cnrs.fr. ORCID
  15. Christophe Duranton: Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France. christophe.duranton@univ-cotedazur.fr. ORCID
  16. Hang Korng Ea: Université Paris Cité, INSERM UMR-1132, Bioscar, Hôpital Lariboisière, AP-HP, Paris, France. hang-korng.ea@aphp.fr. ORCID
PMID: 39294178 DOI: 10.1038/s41467-024-52543-8

Abstract

Deposition of monosodium urate and calcium pyrophosphate (MSU and CPP) micro-crystals is responsible for painful and recurrent inflammation flares in gout and chondrocalcinosis. In these pathologies, the inflammatory reactions are due to the activation of macrophages responsible for releasing various cytokines including IL-1β. The maturation of IL-1β is mediated by the multiprotein NLRP3 inflammasome. Here, we find that activation of the NLRP3 inflammasome by crystals and concomitant production of IL-1β depend on cell volume regulation via activation of the osmo-sensitive LRRC8 anion channels. Both pharmacological inhibition and genetic silencing of LRRC8 abolish NLRP3 inflammasome activation by crystals in vitro and in mouse models of crystal-induced inflammation. Activation of LRRC8 upon MSU/CPP crystal exposure induces ATP release, P2Y receptor activation and intracellular calcium increase necessary for NLRP3 inflammasome activation and IL-1β maturation. We identify a function of the LRRC8 osmo-sensitive anion channels with pathophysiological relevance in the context of joint crystal-induced inflammation.

References

  1. Dalbeth, N., Gosling, A. L., Gaffo, A. & Abhishek, A. Gout. Lancet 397, 1843–1855 (2021). [DOI: 10.1016/S0140-6736(21)00569-9]
  2. Doherty, M. et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet 392, 1403–1412 (2018). [DOI: 10.1016/S0140-6736(18)32158-5]
  3. Latourte, A. et al. Tocilizumab in symptomatic calcium pyrophosphate deposition disease: a pilot study. Ann. Rheum. Dis. 79, 1126–1128 (2020). [DOI: 10.1136/annrheumdis-2020-217188]
  4. Martin, W. J., Walton, M. & Harper, J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal–induced murine peritoneal model of acute gout. Arthritis Rheumatism 60, 281–289 (2009). [DOI: 10.1002/art.24185]
  5. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). [DOI: 10.1038/nature04516]
  6. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016). [DOI: 10.1038/nri.2016.58]
  7. Compan, V. et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37, 487–500 (2012). [DOI: 10.1016/j.immuni.2012.06.013]
  8. Ip, W. K. E. & Medzhitov, R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat. Commun. 6, 6931 (2015). [DOI: 10.1038/ncomms7931]
  9. Qiu, Z. et al. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157, 447–458 (2014). [DOI: 10.1016/j.cell.2014.03.024]
  10. Voss, F. K. et al. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344, 634–638 (2014). [DOI: 10.1126/science.1252826]
  11. Lutter, D., Ullrich, F., Lueck, J. C., Kempa, S. & Jentsch, T. J. Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. J. Cell Sci. 130, 1122–1133 (2017). [DOI: 10.1242/jcs.196253]
  12. Syeda, R. et al. LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell 164, 499–511 (2016). [DOI: 10.1016/j.cell.2015.12.031]
  13. Takahashi, H., Yamada, T., Denton, J. S., Strange, K. & Karakas, E. Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly. Elife 12, e82431 (2023). [DOI: 10.7554/eLife.82431]
  14. Liu, H. et al. Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels. Cell Rep. 42, 112926 (2023). [DOI: 10.1016/j.celrep.2023.112926]
  15. Green, J. P. et al. LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation. Elife 9, e59704 (2020). [DOI: 10.7554/eLife.59704]
  16. Renaudin, F. et al. Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages. Ann. Rheum. Dis. 79, 1506–1514 (2020). [DOI: 10.1136/annrheumdis-2020-217342]
  17. Edwards, J. C., Sedgwick, A. D. & Willoughby, D. A. The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. J. Pathol. 134, 147–156 (1981). [DOI: 10.1002/path.1711340205]
  18. Campillo-Gimenez, L. et al. Inflammatory potential of four different phases of calcium pyrophosphate relies on NF-κB Activation and MAPK Pathways. Front Immunol. 9, 2248 (2018). [DOI: 10.3389/fimmu.2018.02248]
  19. Savage, D. F. & Stroud, R. M. Structural basis of aquaporin inhibition by mercury. J. Mol. Biol. 368, 607–617 (2007). [DOI: 10.1016/j.jmb.2007.02.070]
  20. Friard, J. et al. Comparative effects of chloride channel inhibitors on LRRC8/VRAC-mediated chloride conductance. Front. Pharmacol. 8, 328 (2017).
  21. Decher, N. et al. DCPIB is a novel selective blocker of I(Cl,swell) and prevents swelling-induced shortening of guinea-pig atrial action potential duration. Br. J. Pharm. 134, 1467–1479 (2001). [DOI: 10.1038/sj.bjp.0704413]
  22. Lück, J. C., Puchkov, D., Ullrich, F. & Jentsch, T. J. LRRC8/VRAC anion channels are required for late stages of spermatid development in mice. J. Biol. Chem. 293, 11796–11808 (2018). [DOI: 10.1074/jbc.RA118.003853]
  23. Stuhlmann, T., Planells-Cases, R. & Jentsch, T. J. LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion. Nat. Commun. 9, 1974 (2018). [DOI: 10.1038/s41467-018-04353-y]
  24. Riteau, N. et al. ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation. Cell Death Dis. 3, e403 (2012). [DOI: 10.1038/cddis.2012.144]
  25. Ollivier, M. et al. P2X-GCaMPs as versatile tools for imaging extracellular ATP signaling. eNeuro 8, ENEURO.0185-20.2020 (2021).
  26. Murakami, T. et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl Acad. Sci. 109, 11282–11287 (2012). [DOI: 10.1073/pnas.1117765109]
  27. Hoffmann, E. K., Lambert, I. H. & Pedersen, S. F. Physiology of cell volume regulation in vertebrates. Physiol. Rev. 89, 193–277 (2009). [DOI: 10.1152/physrev.00037.2007]
  28. Jentsch, T. J. VRACs and other ion channels and transporters in the regulation of cell volume and beyond. Nat. Rev. Mol. Cell Biol. 17, 293–307 (2016). [DOI: 10.1038/nrm.2016.29]
  29. Shanfield, S., Campbell, P., Baumgarten, M., Bloebaum, R. & Sarmiento, A. Synovial fluid osmolality in osteoarthritis and rheumatoid arthritis. Clin. Orthop. Relat. Res. 235, 289–295 (1988).
  30. Bertram, K. L. & Krawetz, R. J. Osmolarity regulates chondrogenic differentiation potential of synovial fluid derived mesenchymal progenitor cells. Biochem Biophys. Res Commun. 422, 455–461 (2012). [DOI: 10.1016/j.bbrc.2012.05.015]
  31. Petroni, R. C. et al. Hypertonic saline (NaCl 7.5%) reduces lps-induced acute lung injury in rats. Inflammation 38, 2026–2035 (2015). [DOI: 10.1007/s10753-015-0183-4]
  32. Schreibman, D. L. et al. Mannitol and hypertonic saline reduce swelling and modulate inflammatory markers in a rat model of intracerebral hemorrhage. Neurocrit Care 29, 253–263 (2018). [DOI: 10.1007/s12028-018-0535-7]
  33. Schorn, C. et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 286, 35–41 (2011). [DOI: 10.1074/jbc.M110.139048]
  34. Rabolli, V. et al. Critical role of aquaporins in interleukin 1β (IL-1β)-induced inflammation. J. Biol. Chem. 289, 13937–13947 (2014). [DOI: 10.1074/jbc.M113.534594]
  35. da Silva, I. V. et al. Aquaporin-3 is involved in NLRP3-inflammasome activation contributing to the setting of inflammatory response. Cell Mol. Life Sci. 78, 3073–3085 (2021). [DOI: 10.1007/s00018-020-03708-3]
  36. Burow, P., Klapperstück, M. & Markwardt, F. Activation of ATP secretion via volume-regulated anion channels by sphingosine-1-phosphate in RAW macrophages. Pflug. Arch. 467, 1215–1226 (2015). [DOI: 10.1007/s00424-014-1561-8]
  37. Tang, T. et al. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat. Commun. 8, 202 (2017). [DOI: 10.1038/s41467-017-00227-x]
  38. Domingo-Fernández, R., Coll, R. C., Kearney, J., Breit, S. & O’Neill, L. A. J. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. J. Biol. Chem. 292, 12077–12087 (2017). [DOI: 10.1074/jbc.M117.797126]
  39. Friard, J. et al. LRRC8/VRAC channels exhibit a noncanonical permeability to glutathione, which modulates epithelial-to-mesenchymal transition (EMT). Cell Death Dis 10, 925 (2019).
  40. Zhou, C. et al. Transfer of cGAMP into bystander cells via LRRC8 volume-regulated anion channels augments sting-mediated interferon responses and anti-viral immunity. Immunity 52, 767–781.e6 (2020). [DOI: 10.1016/j.immuni.2020.03.016]
  41. Hyzinski-García, M. C., Rudkouskaya, A. & Mongin, A. A. LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. J. Physiol. 592, 4855–4862 (2014). [DOI: 10.1113/jphysiol.2014.278887]
  42. Gaitán-Peñas, H. et al. Investigation of LRRC8-mediated volume-regulated anion currents in xenopus oocytes. Biophys. J. 111, 1429–1443 (2016). [DOI: 10.1016/j.bpj.2016.08.030]
  43. Ferrari, D. et al. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J. Immunol. 159, 1451–1458 (1997). [DOI: 10.4049/jimmunol.159.3.1451]
  44. Di Virgilio, F. Liaisons dangereuses: P2X7 and the inflammasome. Trends Pharmacol. Sci. 28, 465–472 (2007). [DOI: 10.1016/j.tips.2007.07.002]
  45. Baron, L. et al. The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine. Cell Death Dis. 6, e1629 (2015). [DOI: 10.1038/cddis.2014.576]
  46. Sil, P. et al. P2Y6 receptor antagonist MRS2578 inhibits neutrophil activation and aggregated neutrophil extracellular trap formation induced by gout-associated monosodium urate crystals. J. Immunol. 198, 428–442 (2017). [DOI: 10.4049/jimmunol.1600766]
  47. Uratsuji, H. et al. P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals. J. Immunol. 188, 436–444 (2012). [DOI: 10.4049/jimmunol.1003746]
  48. Lee, G.-S. et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123–127 (2012). [DOI: 10.1038/nature11588]
  49. Triantafilou, K., Hughes, T. R., Triantafilou, M. & Morgan, B. P. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J. Cell Sci. 126, 2903–2913 (2013). [PMID: 23613465]
  50. Gong, T., Yang, Y., Jin, T., Jiang, W. & Zhou, R. Orchestration of NLRP3 inflammasome activation by ion fluxes. Trends Immunol. 39, 393–406 (2018). [DOI: 10.1016/j.it.2018.01.009]
  51. Yaron, J. R. et al. K+ regulates Ca2+ to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis. 6, e1954–e1954 (2015). [DOI: 10.1038/cddis.2015.277]
  52. Camello-Almaraz, C., Gomez-Pinilla, P. J., Pozo, M. J. & Camello, P. J. Mitochondrial reactive oxygen species and Ca2+ signaling. Am. J. Physiol.-Cell Physiol. 291, C1082–C1088 (2006). [DOI: 10.1152/ajpcell.00217.2006]
  53. Duranton, C., Huber, S. M. & Lang, F. Oxidation induces a Cl(-)-dependent cation conductance in human red blood cells. J. Physiol. 539, 847–855 (2002). [DOI: 10.1113/jphysiol.2001.013040]
  54. Capó-Aponte, J. E., Iserovich, P. & Reinach, P. S. Characterization of regulatory volume behavior by fluorescence quenching in human corneal epithelial cells. J. Membr. Biol. 207, 11–22 (2005). [DOI: 10.1007/s00232-005-0800-5]
  55. Untergasser, A. et al. Primer3–new capabilities and interfaces. Nucleic Acids Res. 40, e115 (2012). [DOI: 10.1093/nar/gks596]

Grants

  1. ANR-22-CE14-0020/Agence Nationale de la Recherche (French National Research Agency)
  2. ANR-22-CE14-0020/Agence Nationale de la Recherche (French National Research Agency)
  3. ANR-22-CE14-0020/Agence Nationale de la Recherche (French National Research Agency)
  4. ANR-22-CE14-0020/Agence Nationale de la Recherche (French National Research Agency)

MeSH Term

Animals
NLR Family, Pyrin Domain-Containing 3 Protein
Macrophages
Mice
Inflammasomes
Interleukin-1beta
Humans
Membrane Proteins
Inflammation
Uric Acid
Mice, Inbred C57BL
Calcium
Male

Chemicals

NLR Family, Pyrin Domain-Containing 3 Protein
Inflammasomes
Interleukin-1beta
LRRC8A protein, mouse
Membrane Proteins
Uric Acid
LRRC8A protein, human
Nlrp3 protein, mouse
Calcium
Journal Article
Article has an altmetric score of 7

Word Cloud

Created with Highcharts 10.0.0activationLRRC8inflammationIL-1βNLRP3inflammasomeosmo-sensitiveanionchannelscalciumresponsiblemacrophagesmaturationcrystalscrystal-inducedActivationjointDepositionmonosodiumuratepyrophosphateMSUCPPmicro-crystalspainfulrecurrentflaresgoutchondrocalcinosispathologiesinflammatoryreactionsduereleasingvariouscytokinesincludingmediatedmultiproteinfindconcomitantproductiondependcellvolumeregulationviapharmacologicalinhibitiongeneticsilencingabolishvitromousemodelsuponMSU/CPPcrystalexposureinducesATPreleaseP2Yreceptorintracellularincreasenecessaryidentifyfunctionpathophysiologicalrelevancecontextimportantmicro-crystallin

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