Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

Abstract

Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1β and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Bruton’s tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome. The FDA-approved BTK inhibitor ibrutinib (PCI-32765) efficiently suppresses infarct volume growth and neurological damage in a brain ischaemia/reperfusion model in mice. Ibrutinib inhibits maturation of IL-1β by suppressing caspase-1 activation in infiltrating macrophages and neutrophils in the infarcted area of ischaemic brain. Our study indicates that BTK is essential for NLRP3 inflammasome activation and could be a potent therapeutic target in ischaemic stroke.

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References 61

1. 1.

   Moskowitz M. A., Lo E. H. & Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010 ).

   Not in our library10.1016/j.neuron.2010.07.002

2. 2.

   Eltzschig H. K. & Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat. Med. 17, 1391–1401 (2011 ).

   Not in our library10.1038/nm.2507

3. 3.

   Iadecola C. & Anrather J. The immunology of stroke: from mechanisms to translation. Nat. Med. 17, 796–808 (2011 ).

   Not in our library10.1038/nm.2399

4. 4.

   Shichita T. et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946–950 (2009 ).

   Not in our library10.1038/nm.1999

5. 5.

   Shichita T., Sakaguchi R., Suzuki M. & Yoshimura A. Post-ischemic inflammation in the brain. Front. Immunol. 3, 132 (2012 ).

   Not in our library10.3389/fimmu.2012.00132

6. 6.

   Clarkson B. D. et al. T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. J. Exp. Med. 211, 595–604 (2014 ).

   Not in our library10.1084/jem.20131377

7. 7.
   Post-ischemic inflammation regulates neural damage and protection · 2014

   No notice
8. 8.

   Keller M., Ruegg A., Werner S. & Beer H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008 ).

   Not in our library10.1016/j.cell.2007.12.040

9. 9.

   Schroder K. & Tschopp J. The inflammasomes. Cell 140, 821–832 (2010 ).

   Not in our library10.1016/j.cell.2010.01.040

10. 10.

    Williams A., Flavell R. A. & Eisenbarth S. C. The role of NOD-like receptors in shaping adaptive immunity. Curr. Opin. Immunol. 22, 34–40 (2010 ).

    Not in our library10.1016/j.coi.2010.01.004

11. 11.

    Strowig T., Henao-Mejia J., Elinav E. & Flavell R. Inflammasomes in health and disease. Nature 481, 278–286 (2012 ).

    Not in our library10.1038/nature10759

12. 12.

    Boutin H. et al. Role of IL-1alpha and IL-1beta in ischemic brain damage. J. Neurosci. 21, 5528–5534 (2001 ).

    Not in our library10.1523/jneurosci.21-15-05528.2001

13. 13.

    Schielke G. P., Yang G. Y., Shivers B. D. & Betz A. L. Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J. Cereb. Blood Flow Metab. 18, 180–185 (1998 ).

    Not in our library10.1097/00004647-199802000-00009

14. 14.

    Yang F. et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J. Cereb. Blood Flow Metab. 34, 660–667 (2014 ).

    Not in our library10.1038/jcbfm.2013.242

15. 15.

    Olsson S. et al. Genetic variation within the interleukin-1 gene cluster and ischemic stroke. Stroke 43, 2278–2282 (2012 ).

    Not in our library10.1161/strokeaha.111.647446

16. 16.

    Bauernfeind F. G. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009 ).

    Not in our library10.4049/jimmunol.0901363

17. 17.

    Bauernfeind F. et al. Inflammasomes: current understanding and open questions. Cell. Mol. Life Sci. 68, 765–783 (2011 ).

    Not in our library10.1007/s00018-010-0567-4

18. 18.
    Encephalomyocarditis Virus Viroporin 2B Activates NLRP3 Inflammasome · 2012

    No notice
19. 19.

    Eisenbarth S. C., Colegio O. R., O'Connor W., Sutterwala F. S. & Flavell R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008 ).

    Not in our library10.1038/nature06939

20. 20.

    Hornung V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008 ).

    Not in our library10.1038/ni.1631

21. 21.

    Lu B. et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature 488, 670–674 (2012 ).

    Not in our library10.1038/nature11290

22. 22.

    Qu Y. et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490, 539–542 (2012 ).

    Not in our library10.1038/nature11429

23. 23.

    Chuang Y. T. et al. Tumor suppressor death-associated protein kinase is required for full IL-1beta production. Blood 117, 960–970 (2011 ).

    Not in our library10.1182/blood-2010-08-303115

24. 24.

    Lin K. M. et al. IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc. Natl Acad. Si. USA 111, 775–780 (2014 ).

    Not in our library10.1073/pnas.1320294111

25. 25.

    Gross O. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009 ).

    Not in our library10.1038/nature07965

26. 26.

    Okada M., Matsuzawa A., Yoshimura A. & Ichijo H. Lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. J. Biol. Chem. 289, 32926–32936 (2014 ).

    Not in our library10.1074/jbc.m114.579961

27. 27.

    Hara H. et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 14, 1247–1255 (2013 ).

    Not in our library10.1038/ni.2749

28. 28.

    Jefferies C. A. et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J. Biol. Chem. 278, 26258–26264 (2003 ).

    Not in our library10.1074/jbc.m301484200

29. 29.

    Lee K. G. et al. Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response. Proc. Natl Acad. Sci. USA 109, 5791–5796 (2012 ).

    Not in our library10.1073/pnas.1119238109

30. 30.

    Jefferies C. A. & O'Neill L. A. Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Immunol. Lett. 92, 15–22 (2004 ).

    Not in our library10.1016/j.imlet.2003.11.017

31. 31.

    Mohamed A. J. et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol. Rev. 228, 58–73 (2009 ).

    Not in our library10.1111/j.1600-065x.2008.00741.x

32. 32.

    Mohamed A. J., Nore B. F., Christensson B. & Smith C. I. Signalling of Bruton's tyrosine kinase, Btk. Scand. J. Immunol. 49, 113–118 (1999 ).

    Not in our library10.1046/j.1365-3083.1999.00504.x

33. 33.

    Herrera A. F. & Jacobsen E. D. Ibrutinib for the treatment of mantle cell lymphoma. Clin. Cancer Res. 20, 5365–5371 (2014 ).

    Not in our library10.1158/1078-0432.ccr-14-0010

34. 34.

    Mangla A. et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood 104, 1191–1197 (2004 ).

    Not in our library10.1182/blood-2004-01-0207

35. 35.

    van de Veerdonk F. L. et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum. 63, 1507–1516 (2011 ).

    Not in our library10.1002/art.30314

36. 36.
    The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells · 2011

    No notice
37. 37.

    Vargas L., Hamasy A., Nore B. F. & Smith C. I. Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Scand. J. Immunol. 78, 130–139 (2013 ).

    Not in our library10.1111/sji.12069

38. 38.

    Thomas J. D. et al. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261, 355–358 (1993 ).

    Not in our library10.1126/science.8332900

39. 39.

    Fernandes-Alnemri T. et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat. Immunol. 11, 385–393 (2010 ).

    Not in our library10.1038/ni.1859

40. 40.

    Freigang S. et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat. Immunol. 14, 1045–1053 (2013 ).

    Not in our library10.1038/ni.2704

41. 41.

    Zhang W. H. et al. Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc. Natl Acad. Sci. USA 100, 16012–16017 (2003 ).

    Not in our library10.1073/pnas.2534856100

42. 42.

    Ross J., Brough D., Gibson R. M., Loddick S. A. & Rothwell N. J. A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology 53, 638–642 (2007 ).

    Not in our library10.1016/j.neuropharm.2007.07.015

43. 43.

    Honigberg L. A. et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl Acad. Sci. USA 107, 13075–13080 (2010 ).

    Not in our library10.1073/pnas.1004594107

44. 44.

    Mankan A. K., Dau T., Jenne D. & Hornung V. The NLRP3/ASC/Caspase-1 axis regulates IL-1beta processing in neutrophils. Eur. J. Immunol. 42, 710–715 (2012 ).

    Not in our library10.1002/eji.201141921

45. 45.

    Neumann K. & Ruland J. Kinases conquer the inflammasomes. Nat. Immunol. 14, 1207–1208 (2013 ).

    Not in our library10.1038/ni.2763

46. 46.

    Hasegawa E. et al. IL-23-independent induction of IL-17 from gammadeltaT cells and innate lymphoid cells promotes experimental intraocular neovascularization. J. Immunol. 190, 1778–1787 (2013 ).

    Not in our library10.4049/jimmunol.1202495

47. 47.

    Sutton C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009 ).

    Not in our library10.1016/j.immuni.2009.08.001

48. 48.

    Shichita T. et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat. Med. 18, 911–917 (2012 ).

    Not in our library10.1038/nm.2749

49. 49.

    Hedtjarn M., Mallard C. & Hagberg H. Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J. Cereb. Blood Flow Metab. 24, 1333–1351 (2004 ).

    Not in our library10.1097/01.wcb.0000141559.17620.36

50. 50.

    Chen Y. et al. Intrastriatal B-cell administration limits infarct size after stroke in B-cell deficient mice. Metab. Brain Dis. 27, 487–493 (2012 ).

    Not in our library10.1007/s11011-012-9317-7

51. 51.

    Dinarello C. A. Interleukin-1beta and the autoinflammatory diseases. N. Engl. J. Med. 360, 2467–2470 (2009 ).

    Not in our library10.1056/nejme0811014

52. 52.
    Inflammasomes in neuroinflammation and changes in brain function: a focused review · 2014

    No notice
53. 53.

    Dinarello C. A. & van der Meer J. W. Treating inflammation by blocking interleukin-1 in humans. Semin. Immunol. 25, 469–484 (2013 ).

    Not in our library10.1016/j.smim.2013.10.008

54. 54.
    Ibrutinib and novel BTK inhibitors in clinical development · 2013

    No notice
55. 55.

    Horai R. et al. Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998 ).

    Not in our library10.1084/jem.187.9.1463

56. 56.

    Koga K. et al. Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein. Immunity 30, 372–383 (2009 ).

    Not in our library10.1016/j.immuni.2008.12.021

57. 57.

    Morita R. et al. ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. Proc. Natl Acad. Sci. USA 112, 160–165 (2015 ).

    Not in our library10.1073/pnas.1413234112

58. 58.

    Heinonen J. E., Smith C. I. & Nore B. F. Silencing of Bruton's tyrosine kinase (Btk) using short interfering RNA duplexes (siRNA). FEBS Lett. 527, 274–278 (2002 ).

    Not in our library10.1016/s0014-5793(02)03206-4

59. 59.

    Shenoy A. R. et al. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336, 481–485 (2012 ).

    Not in our library10.1126/science.1217141

60. 60.

    Bederson J. B. et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17, 472–476 (1986 ).

    Not in our library10.1161/01.str.17.3.472

61. 61.

    Tamiya T. et al. Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. J. Immunol. 191, 2360–2371 (2013 ).

    Not in our library10.4049/jimmunol.1301276

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