, Volume 41, Issue 4, pp 1321–1333 | Cite as

NLRP3 Inflammasome Involves in the Acute Exacerbation of Patients with Chronic Obstructive Pulmonary Disease

  • Huaying Wang
  • Chun’er Lv
  • Shi Wang
  • Huajuan Ying
  • Yuesong Weng
  • Wanjun Yu


The NLR pyrin domain-containing protein 3 (NLRP3) inflammasome, a multi-protein complex, produces the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which may contribute to the development of airway inflammation in chronic obstructive pulmonary disease (COPD). The aim of this study was to explore the correlation between circulating and local airway NLRP3 inflammasome activation with acute exacerbation of COPD (AECOPD). mRNA levels of NLRP3, Caspase (Casp)-1, apoptosis-associated speck-like protein containing CARD (ASC), IL-18, and IL-1β in peripheral blood mononuclear cells (PBMCs) and bronchial tissues were determined by real-time PCR in 32 smokers, 65 patients with AECOPD, 50 COPD patients in recovery stage, and 30 COPD patients in stable stage. The levels of IL-1β and IL-18 in serum and bronchoalveolar lavage fluid (BALF) supernatants were measured by ELISA. The load of six common pathogens in BALF samples were determined by real-time PCR. The potential correlation between the mRNA levels of NLRP3, Casp-1, ASC, IL-18 or IL-1β and the load of pathogens was evaluated individually. Significantly higher mRNA levels of NLRP3, Casp-1, ASC, IL-18, IL-1β and higher levels of IL-18 and IL-1β were found in patients with AECOPD than in smokers. These NLRP3 inflammasome mediators were significantly decreased when COPD patients in the same group became clinical stable. The increased mRNA levels of NLRP3 inflammasomes in bronchial tissues were positively correlated with the load of the six common pathogens in the lower respiratory tract. We conclude that systemic and local airway NLRP3 inflammasome activation is associated with the acute exacerbation, which might be predictive factors of the acute exacerbation and clinical outcomes in COPD patients.


chronic obstructive pulmonary disease (COPD) NLRP3 inflammasome acute exacerbation predictive factors 



This study was funded by the Nature Scientific Fund of Ningbo City (2013A610237 and 2015A610310) and the Medical Science and Technology Project of Zhejiang Province (2017KY617), China.

Compliance with Ethical Standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics and research committee of the Affiliated Yinzhou Hospital, College of Medicine, Ningbo University, China and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hogg, J.C., and W. Timens. 2009. The pathology of chronic obstructive pulmonary disease. Annual Review of Pathology 4: 435–459.CrossRefPubMedGoogle Scholar
  2. 2.
    Mathers, C.D., and D. Loncar. 2006. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Medicine 3: e442.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Beasley, V., P.V. Joshi, A. Singanayagam, P.L. Molyneaux, S.L. Johnston, and P. Mallia. 2012. Lung microbiology and exacerbations in COPD. International Journal of Chronic Obstructive Pulmonary Disease 7: 555–569.PubMedPubMedCentralGoogle Scholar
  4. 4.
    De Nardo, D., C.M. De Nardo, and E. Latz. 2014. New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease. The American Journal of Pathology 84: 42–54.CrossRefGoogle Scholar
  5. 5.
    Martinon, F., K. Burns, and J. Tschopp. 2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular Cell 10: 417–426.CrossRefPubMedGoogle Scholar
  6. 6.
    van de Veerdonk, F., M. Netea, C. Dinarello, and L. Joosten. 2011. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends in Immunology 32: 110–116.CrossRefPubMedGoogle Scholar
  7. 7.
    Ritter, M., K. Straubinger, S. Schmidt, D.H. Busch, S. Hagner, H. Garn, C. Prazeres da Costa, and L.E. Layland. 2014. Functional relevance of NLRP3 inflammasome-mediated interleukin (IL)-1β during acute allergic airway inflammation. Clinical and Experimental Immunology 178: 212–223.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nieto-Torres, J.L., C. Verdiá-Báguena, J.M. Jimenez-Guardeño, J.A. Regla-Nava, C. Castaño-Rodriguez, R. Fernandez-Delgado, J. Torres, V.M. Aguilella, and L. Enjuanes. 2015. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 485: 330–339.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li, C., H. Zhihong, L. Wenlong, L. Xiaoyan, C. Qing, L. Wenzhi, X. Siming, and L. Shengming. 2016. The NLRP3 Inflammasome Regulates Bronchial Epithelial Cell Injury and Pro-apoptosis After Exposure to Biomass Fuel Smoke. American Journal of Respiratory Cell and Molecular Biology 55 (6): 815–824.CrossRefPubMedGoogle Scholar
  10. 10.
    Domej, W., Z. Foldes-Papp, E. Flogel, and B. Haditsch. 2006. Chronic obstructive pulmonary disease and oxidative stress. Current Pharmaceutical Biotechnology 7: 117–123.CrossRefPubMedGoogle Scholar
  11. 11.
    Müller, T., R.P. Vieira, M. Grimm, T. Dürk, S. Cicko, R. Zeiser, T. Jakob, S.F. Martin, B. Blumenthal, S. Sorichter, D. Ferrari, F. Di Virgillio, and M. Idzko. 2011. A potential role for P2X7R in allergic airway inflammation in mice and humans. American Journal of Respiratory Cell and Molecular Biology 44: 456–464.CrossRefPubMedGoogle Scholar
  12. 12.
    Faner, R., P. Sobradillo, A. Noguera, C. Gomez, T. Cruz, A. López-Giraldo, E. Ballester, N. Soler, J.I. Arostegui, P. Pelegrín, R. Rodriguez-Roisin, J. Yagüe, B.G. Cosio, M. Juan, and A. Agustí. 2016. The inflammasome pathway in stable COPD and acute exacerbations. ERJ Open Research 2: 00002–02016.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rabe, K.F., S. Hurd, A. Anzueto, P.J. Barnes, S.A. Buist, P. Calverley, Y. Fukuchi, C. Jenkins, R. Rodriguez-Roisin, C. van Weel, and J. Zielinski. 2007. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American Journal of Respiratory and Critical Care Medicine 176: 532–555.CrossRefPubMedGoogle Scholar
  14. 14.
    Anthonisen, N.R., J. Manfreda, C.P. Warren, E.S. Hershfield, G.K. Harding, and N.A. Nelson. 1987. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Annals of Internal Medicine 106: 196–204.CrossRefPubMedGoogle Scholar
  15. 15.
    Rodriguez-Roisin, R. 2000. Toward a consensus definition for COPD exacerbations. Chest 117: 398S–401S.CrossRefPubMedGoogle Scholar
  16. 16.
    Hussain, S., S. Sangtian, S.M. Anderson, R.J. Snyder, J.D. Marshburn, A.B. Rice, J.C. Bonner, and S. Garantziotis. 2014. Inflammasome activation in airway epithelial cells after multi-walled carbon nanotube exposure mediates a profibrotic response in lung fibroblasts. Particle and Fibre Toxicology 11: 28.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dihlmann, S., P. Erhart, A. Mehrabi, A. Nickkholgh, F. Lasitschka, D. Böckler, and M. Hakimi. 2014. Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms. Molecular Medicine 20: 230–237.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wang, H., X. Gu, Y. Weng, T. Xu, Z. Fu, W. Peng, and W. Yu. 2015. Quantitative analysis of pathogens in the lower respiratory tract of patients with chronic obstructive pulmonary disease. BMC Pulmonary Medicine 15: 94. Scholar
  19. 19.
    Rathinam, V.A., S.K. Vanaja, and K.A. Fitzgerald. 2012. Regulation of inflammasome signaling. Nature Immunology 13: 333–342.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kim, R.Y., J.W. Pinkerton, P.G. Gibson, M.A. Cooper, J.C. Horvat, and P.M. Hansbro. 2015. Inflammasomes in COPD and neutrophilic asthma. Thorax 70: 1199–1201.CrossRefPubMedGoogle Scholar
  21. 21.
    Hosseinian, N., Y. Cho, R.F. Lockey, and N. Kolliputi. 2015. The role of the NLRP3 inflammasome in pulmonary diseases. Therapeutic Advances in Respiratory Disease 9: 188–197.CrossRefPubMedGoogle Scholar
  22. 22.
    Dinarello, C.A. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 27: 519–550.CrossRefPubMedGoogle Scholar
  23. 23.
    Sims, J.E., and D.E. Smith. 2010. The IL-1 family: regulators of immunity. Nature Reviews. Immunology 10: 89–102.CrossRefPubMedGoogle Scholar
  24. 24.
    Kang, M., R.J. Homer, A. Gallo, C.G. Lee, K.A. Crothers, Sj Cho, C. Rochester, H. Cain, G. Chupp, H.J. Yoon, and J.A. Elias. 2007. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. Journal of Immunology 178: 1948–1959.CrossRefGoogle Scholar
  25. 25.
    Petersen, A.M., M. Penkowa, M. Iversen, L. Frydelund-Larsen, J.L. Andersen, J. Mortensen, P. Lange, and B.K. Pedersen. 2007. Elevated levels of IL-18 in plasma and skeletal muscle in chronic obstructive pulmonary disease. Lung 185: 161–171.CrossRefPubMedGoogle Scholar
  26. 26.
    Rovina, N., E. Dima, C. Gerassimou, A. Kollintza, C. Gratziou, and C. Roussos. 2009. Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease. Respiratory Medicine 103: 1056–1062.CrossRefPubMedGoogle Scholar
  27. 27.
    Imaoka, H., T. Hoshino, S. Takei, T. Kinoshita, M. Okamoto, T. Kawayama, S. Kato, H. Iwasaki, K. Watanabe, and H. Aizawa. 2008. Interleukin-18 production and pulmonary function in COPD. The European Respiratory Journal 31: 287–297.CrossRefPubMedGoogle Scholar
  28. 28.
    Bryan, N.B., A. Dorfleutner, Y. Rojanasakul, and C. Stehlik. 2009. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. Journal of Immunology 182: 3173–3182.CrossRefGoogle Scholar
  29. 29.
    Eltom, S., M.G. Belvisi, C.S. Stevenson, S.A. Maher, E. Dubuis, K.A. Fitzgerald, and M.A. Birrell. 2014. Role of the Inflammasome-Caspase1/11-IL-1/18Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD. PLoS One 9: e112829.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Franchi, L., T.-D. Kanneganti, G.R. Dubyak, and G. Nuñez. 2007. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. The Journal of Biological Chemistry 282: 18810–18818.CrossRefPubMedGoogle Scholar
  31. 31.
    Harder, J., L. Franchi, R. Muñoz-Planillo, J.H. Park, T. Reimer, and G. Núñez. 2009. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. Journal of Immunology 183: 5823–5829.CrossRefGoogle Scholar
  32. 32.
    Kumar, H., Y. Kumagai, T. Tsuchida, P.A. Koenig, T. Satoh, Z. Guo, M.H. Jang, T. Saitoh, S. Akira, and T. Kawai. 2009. Involvement of the NLRP3 inflammasome in innate and humoral adaptiveimmune responses to fungal beta-glucan. Journal of Immunology 183: 8061–8067.CrossRefGoogle Scholar
  33. 33.
    McNeela, E.A., A. Burke, D.R. Neill, C. Baxter, V.E. Fernandes, D. Ferreira, S. Smeaton, R. El-Rachkidy, R.M. McLoughlin, A. Mori, B. Moran, K.A. Fitzgerald, J. Tschopp, V. Pétrilli, P.W. Andrew, A. Kadioglu, and E.C. Lavelle. 2010. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathogens 6: e1001191.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Perret, M., C. Badiou, G. Lina, S. Burbaud, Y. Benito, M. Bes, V. Cottin, F. Couzon, C. Juruj, O. Dauwalder, N. Goutagny, B.A. Diep, F. Vandenesch, and T. Henry. 2012. Cross-talk between Staphylococcus aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner. Cellular Microbiology 14: 1019–1036.CrossRefPubMedGoogle Scholar
  35. 35.
    Willingham, S.B., I.C. Allen, D.T. Bergstralh, W.J. Brickey, M.T. Huang, D.J. Taxman, J.A. Duncan, and J.P. Ting. 2009. NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. Journal of Immunology 183: 2008–2015.CrossRefGoogle Scholar
  36. 36.
    Wonnenberg, B., T. Tschernig, M. Voss, M. Bischoff, C. Meier, S.H. Schirmer, F. Langer, R. Bals, and C. Beisswenger. 2014. Probenecid reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia. International Journal of Medical Microbiology 304: 725–729.CrossRefPubMedGoogle Scholar
  37. 37.
    Rotta Detto Loria, J., K. Rohmann, D. Droemann, P. Kujath, J. Rupp, T. Goldmann, and K. Dalhoff. 2013. Non-typeable haemophilus influenzae infection upregulates the NLRP3 inflammasome and leads to Caspase-1-dependent secretion of interleukin-1β—A possible pathway of exacerbations in COPD. PLoS One 8: e66818.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yang, W., H. Ni, H. Wang, and H. Gu. 2015. NLRP3 inflammasome is essential for the development of chronic obstructive pulmonary disease. International Journal of Clinical and Experimental Pathology 8: 13209–13216.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Respiratory Diseases, Affiliated Yinzhou Hospital, College of MedicineNingbo UniversityNingbo CityChina
  2. 2.Clinical LaboratoryFirst HospitalNingbo CityChina

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