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Niclosamide activates the NLRP3 inflammasome by intracellular acidification and mitochondrial inhibition

Communications biology v.2 , 2019년, pp.2 -   
Thi Tran, Uyen (YCI Laboratory for Cellular Bioenergetic Network, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan ) ;  Kitami, Toshimori ( YCI Laboratory for Cellular Bioenergetic Network, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan)
Abstract

The NLRP3 inflammasome is unique among pattern recognition receptors in using changes in cellular physiology as a mechanism for sensing host danger. To dissect the physiological network controlling inflammasome activation, we screened for small-molecule activators and suppressors of IL-1β release in macrophages. Here we identified niclosamide, a mitochondrial uncoupler, as an activator of NLRP3 inflammasome. We find that niclosamide inhibits mitochondria and induces intracellular acidification, both of which are necessary for inflammasome activation. Intracellular acidification, by inhibiting glycolysis, works together with mitochondrial inhibition to induce intracellular ATP loss, which compromises intracellular potassium maintenance, a key event to NLRP3 inflammasome activation. A modest decline in intracellular ATP or pH within an optimal range induces maximum IL-1β release while their excessive decline suppresses IL-1β release. Our work illustrates how energy metabolism converges upon intracellular potassium to activate NLRP3 inflammasome and highlights a biphasic relationship between cellular physiology and IL-1β release.Uyen Thi Tran and Toshimori Kitami show that niclosamide activates the NLRP3 inflammasome through a modest intracellular acidification or ATP loss while an excessive decline of intracellular pH or ATP suppresses it. This study uncovers a biphasic immune response that accommodates cellular energy level.

  

참고문헌 (55)

  1. 1. 1. Martinon F Burns K Tschopp J The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta Mol. Cell 2002 10 417 426 10.1016/S1097-2765(02)00599-3 12191486 
  2. 2. 2. Broz P Dixit VM Inflammasomes: mechanism of assembly, regulation and signalling Nat. Rev. Immunol. 2016 16 407 420 10.1038/nri.2016.58 27291964 
  3. 3. 3. Liston A Masters SL Homeostasis-altering molecular processes as mechanisms of inflammasome activation Nat. Rev. Immunol. 2017 17 208 214 10.1038/nri.2016.151 28163301 
  4. 4. 4. Duewell P NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals Nature 2010 464 1357 1361 10.1038/nature08938 20428172 
  5. 5. 5. Wen H Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling Nat. Immunol. 2011 12 408 415 10.1038/ni.2022 21478880 
  6. 6. 6. Vandanmagsar B The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance Nat. Med. 2011 17 179 188 10.1038/nm.2279 21217695 
  7. 7. 7. Masters SL Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes Nat. Immunol. 2010 11 897 904 10.1038/ni.1935 20835230 
  8. 8. 8. Heneka MT NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice Nature 2013 493 674 678 10.1038/nature11729 23254930 
  9. 9. 9. Martinon F Petrilli V Mayor A Tardivel A Tschopp J Gout-associated uric acid crystals activate the NALP3 inflammasome Nature 2006 440 237 241 10.1038/nature04516 16407889 
  10. 10. 10. Dostert C Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica Science 2008 320 674 677 10.1126/science.1156995 18403674 
  11. 11. 11. Larsen CM Interleukin-1-receptor antagonist in type 2 diabetes mellitus New Engl. J. Med. 2007 356 1517 1526 10.1056/NEJMoa065213 17429083 
  12. 12. 12. Ridker PM Antiinflammatory therapy with canakinumab for atherosclerotic disease New Engl. J. Med. 2017 377 1119 1131 10.1056/NEJMoa1707914 28845751 
  13. 13. 13. Jiang H Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders J. Exp. Med. 2017 214 3219 3238 10.1084/jem.20171419 29021150 
  14. 14. 14. Guo H Callaway JB Ting JP Inflammasomes: mechanism of action, role in disease, and therapeutics Nat. Med. 2015 21 677 687 10.1038/nm.3893 26121197 
  15. 15. 15. Munoz-Planillo R K + efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter Immunity 2013 38 1142 1153 10.1016/j.immuni.2013.05.016 23809161 
  16. 16. 16. Petrilli V Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration Cell Death Differ. 2007 14 1583 1589 10.1038/sj.cdd.4402195 17599094 
  17. 17. 17. Zhou R Yazdi AS Menu P Tschopp J A role for mitochondria in NLRP3 inflammasome activation Nature 2011 469 221 225 10.1038/nature09663 21124315 
  18. 18. 18. Hornung V Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization Nat. Immunol. 2008 9 847 856 10.1038/ni.1631 18604214 
  19. 19. 19. Allam R Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming EMBO Rep. 2014 15 982 990 10.15252/embr.201438463 24990442 
  20. 20. 20. Yeh P Tschumi AI Kishony R Functional classification of drugs by properties of their pairwise interactions Nat. Genet. 2006 38 489 494 10.1038/ng1755 16550172 
  21. 21. 21. Farha MA Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase Proc. Natl Acad. Sci. USA 2015 112 11048 11053 10.1073/pnas.1511751112 26283394 
  22. 22. 22. Coll RC A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases Nat. Med. 2015 21 248 255 10.1038/nm.3806 25686105 
  23. 23. 23. Cross AR Jones OT The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils Specif. Label. a Compon. Polypept. oxidase. Biochem. J. 1986 237 111 116 
  24. 24. 24. Leopoldo M Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents J. Med. Chem. 2004 47 6616 6624 10.1021/jm049702f 15588097 
  25. 25. 25. Shimada K Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis Immunity 2012 36 401 414 10.1016/j.immuni.2012.01.009 22342844 
  26. 26. 26. Gohil VM Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis Nat. Biotechnol. 2010 28 249 255 10.1038/nbt.1606 20160716 
  27. 27. 27. Wagner BK Large-scale chemical dissection of mitochondrial function Nat. Biotechnol. 2008 26 343 351 10.1038/nbt1387 18297058 
  28. 28. 28. Jurgeit A Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects PLoS Pathog. 2012 8 e1002976 10.1371/journal.ppat.1002976 23133371 
  29. 29. 29. Ui M A role of phosphofructokinase in pH-dependent regulation of glycolysis Biochim. Biophys. Acta 1966 124 310 322 10.1016/0304-4165(66)90194-2 4226189 
  30. 30. 30. Milligan LP McBride BW Energy costs of ion pumping by animal tissues J. Nutr. 1985 115 1374 1382 10.1093/jn/115.10.1374 2413191 
  31. 31. 31. Matsuyama S Llopis J Deveraux QL Tsien RY Reed JC Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis Nat. Cell Biol. 2000 2 318 325 10.1038/35014006 10854321 
  32. 32. 32. Keller M Ruegg A Werner S Beer HD Active caspase-1 is a regulator of unconventional protein secretion Cell 2008 132 818 831 10.1016/j.cell.2007.12.040 18329368 
  33. 33. 33. Shao W Yeretssian G Doiron K Hussain SN Saleh M The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock J. Biol. Chem. 2007 282 36321 36329 10.1074/jbc.M708182200 17959595 
  34. 34. 34. Duncan JA Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling Proc. Natl Acad. Sci. USA 2007 104 8041 8046 10.1073/pnas.0611496104 17483456 
  35. 35. 35. Mankan AK Dau T Jenne D Hornung V The NLRP3/ASC/Caspase-1 axis regulates IL-1beta processing in neutrophils Eur. J. Immunol. 2012 42 710 715 10.1002/eji.201141921 22213227 
  36. 36. 36. Karmakar M Katsnelson MA Dubyak GR Pearlman E Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1beta secretion in response to ATP Nat. Commun. 2016 7 10555 10.1038/ncomms10555 26877061 
  37. 37. 37. Kool M Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome J. Immunol. 2008 181 3755 3759 10.4049/jimmunol.181.6.3755 18768827 
  38. 38. 38. Sharp FA Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome Proc. Natl Acad. Sci. USA 2009 106 870 875 10.1073/pnas.0804897106 19139407 
  39. 39. 39. Sand J Expression of inflammasome proteins and inflammasome activation occurs in human, but not in murine keratinocytes Cell Death Dis. 2018 9 24 10.1038/s41419-017-0009-4 29348630 
  40. 40. 40. Liu T Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response Cell Rep. 2014 8 974 982 10.1016/j.celrep.2014.07.012 25127135 
  41. 41. 41. Imamura H Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators Proc. Natl Acad. Sci. USA 2009 106 15651 15656 10.1073/pnas.0904764106 19720993 
  42. 42. 42. Tantama M Hung YP Yellen G Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor J. Am. Chem. Soc. 2011 133 10034 10037 10.1021/ja202902d 21631110 
  43. 43. 43. Tannahill GM Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha Nature 2013 496 238 242 10.1038/nature11986 23535595 
  44. 44. 44. Park S Defective mitochondrial fission augments NLRP3 inflammasome activation Sci. Rep. 2015 5 15489 10.1038/srep15489 26489382 
  45. 45. 45. Jabaut J Ather JL Taracanova A Poynter ME Ckless K Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent IL-1beta secretion in association with alterations in cellular redox and energy status Free Radic. Biol. Med. 2013 60 233 245 10.1016/j.freeradbiomed.2013.01.025 23376234 
  46. 46. 46. Kaneko N Applications of reconstituted inflammasomes in a cell-free system to drug discovery and elucidation of the pathogenesis of autoinflammatory diseases Inflamm. Regen. 2017 37 9 10.1186/s41232-017-0040-y 29259708 
  47. 47. 47. Mangan MSJ Targeting the NLRP3 inflammasome in inflammatory diseases Nat. Rev. Drug Discov. 2018 17 588 606 10.1038/nrd.2018.97 30026524 
  48. 48. 48. Isakov E Weisman-Shomer P Benhar M Suppression of the pro-inflammatory NLRP3/interleukin-1beta pathway in macrophages by the thioredoxin reductase inhibitor auranofin Biochim. Biophys. Acta 2014 1840 3153 3161 10.1016/j.bbagen.2014.07.012 25065288 
  49. 49. 49. Lamkanfi M Glyburide inhibits the Cryopyrin/Nalp3 inflammasome J. Cell Biol. 2009 187 61 70 10.1083/jcb.200903124 19805629 
  50. 50. 50. Gonçalves, R. & Mosser, D. M. The isolation and characterization of murine macrophages. Curr. Protoc. Immunol . 111 , 1–16 (2015). 
  51. 51. 51. Sanjana NE Shalem O Zhang F Improved vectors and genome-wide libraries for CRISPR screening Nat. Methods 2014 11 783 784 10.1038/nmeth.3047 25075903 
  52. 52. 52. Kamentsky L Improved structure, function and compatibility for CellProfiler: modular high-throughput image analysis software Bioinformatics 2011 27 1179 1180 10.1093/bioinformatics/btr095 21349861 
  53. 53. 53. Aits S Jaattela M Nylandsted J Methods for the quantification of lysosomal membrane permeabilization: a hallmark of lysosomal cell death Methods Cell Biol. 2015 126 261 285 10.1016/bs.mcb.2014.10.032 25665450 
  54. 54. 54. Rabuffetti M Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines J. Neurosci. 2000 20 4398 4404 10.1523/JNEUROSCI.20-12-04398.2000 10844008 
  55. 55. 55. Tran U Kitami T Data from: niclosamide activates the NLRP3 inflammasome by intracellular acidification and mitochondrial inhibition Dryad Digit. Repos. 2018 10.5061/dryad.mf7qb0c 

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