Inflammation Research

, Volume 62, Issue 11, pp 981–990 | Cite as

Myeloperoxidase deficiency in mice exacerbates lung inflammation induced by nonviable Candida albicans

  • Mizuki Homme
  • Nao Tateno
  • Noriko Miura
  • Naohito Ohno
  • Yasuaki Aratani
Original Research Paper



This study aimed to evaluate the effect of myeloperoxidase (MPO) deficiency on lung inflammation induced by nonviable Candida albicans (nCA).


Mice were inoculated intranasally with nCA, and accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid was analyzed by flow cytometry. The levels of macrophage inflammatory protein 2 (MIP-2), keratinocyte-derived chemokine (KC), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in the lung were measured by ELISA. Production of MIP-2 and KC from neutrophils and macrophages was quantified in vitro. MIP-2 mRNA expression in the neutrophils was analyzed by real-time reverse transcription-PCR, and the extent of phosphorylation of ERK1/2 and Syk in the neutrophils was analyzed by Western blotting.


The MPO−/− mice that received nCA showed more severe pneumonia than wild-type mice. Within 12 h of nCA administration, MPO−/− mice had significantly higher numbers of alveolar neutrophils and increased production of MIP-2 and KC relative to the responses seen in wild-type mice. Neutralization of MIP-2 and KC in vivo significantly reduced neutrophil infiltration. In vitro, production of MIP-2, but not that of KC, was enhanced in the nCA-stimulated neutrophils from MPO−/− mice, concomitant with up-regulation of Syk and ERK1/2. At 1 and 3 days after nCA administration, MPO−/− mice had significantly higher lung concentrations of TNF-α and IL-1β than wild-type mice.


Pulmonary administration of nCA produced an altered inflammatory response in MPO−/− mice relative to wild-type mice. Enhanced MIP-2 production by MPO−/− neutrophils may at least partly contribute to exacerbated inflammation in mutant mice.


Inflammation Myeloperoxidase Neutrophil Candida 



We thank Minami Sugimura for technical support. This work was supported in part by JSPS KAKENHI Grant number 23580406, and a grant from the Japanese Ministry of Health, Labor and Welfare.


  1. 1.
    Brown GD. Innate antifungal immunity: the key role of phagocytes. Annu Rev Immunol. 2011;29:1–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77:598–625.PubMedCrossRefGoogle Scholar
  3. 3.
    Klebanoff SJ, Kettle AJ, Rosen H, Winterbourn CC, Nauseef WM. Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J Leukoc Biol. 2013;93:185–98.PubMedCrossRefGoogle Scholar
  4. 4.
    Aratani Y, Koyama H, Nyui S, Suzuki K, Kura F, Maeda N. Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase. Infect Immun. 1999;67:1828–36.PubMedGoogle Scholar
  5. 5.
    Aratani Y, Kura F, Watanabe H, Akagawa H, Takano Y, Ishida-Okawara A, et al. Contribution of the myeloperoxidase-dependent oxidative system to host defence against Cryptococcus neoformans. J Med Microbiol. 2006;55:1291–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Aratani Y, Kura F, Watanabe H, Akagawa H, Takano Y, Suzuki K, et al. Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus. Med Mycol. 2002;40:557–63.PubMedGoogle Scholar
  7. 7.
    Aratani Y, Kura F, Watanabe H, Akagawa H, Takano Y, Suzuki K, et al. Critical role of myeloperoxidase and nicotinamide adenine dinucleotide phosphate-oxidase in high-burden systemic infection of mice with Candida albicans. J Infect Dis. 2002;185:1833–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Aratani Y, Kura F, Watanabe H, Akagawa H, Takano Y, Suzuki K, et al. Differential host susceptibility to pulmonary infections with bacteria and fungi in mice deficient in myeloperoxidase. J Infect Dis. 2000;182:1276–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J Exp Med. 1997;185:207–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Segal BH, Han W, Bushey JJ, Joo M, Bhatti Z, Feminella J, et al. NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One. 2010;5:e9631.PubMedCrossRefGoogle Scholar
  11. 11.
    Petersen JE, Hiran TS, Goebel WS, Johnson C, Murphy RC, Azmi FH, et al. Enhanced cutaneous inflammatory reactions to Aspergillus fumigatus in a murine model of chronic granulomatous disease. J Invest Dermatol. 2002;118:424–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Komatsu J, Koyama H, Maeda N, Aratani Y. Earlier onset of neutrophil-mediated inflammation in the ultraviolet-exposed skin of mice deficient in myeloperoxidase and NADPH oxidase. Inflamm Res. 2006;55:200–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Takeuchi K, Umeki Y, Matsumoto N, Yamamoto K, Yoshida M, Suzuki K, et al. Severe neutrophil-mediated lung inflammation in myeloperoxidase-deficient mice exposed to zymosan. Inflamm Res. 2012;61:197–205.PubMedCrossRefGoogle Scholar
  14. 14.
    Tateno N, Matsumoto N, Motowaki T, Suzuki K, Aratani Y. Myeloperoxidase deficiency induces MIP-2 production via ERK activation in zymosan-stimulated mouse neutrophils. Free Radic Res. 2013;47:376–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Shepherd MG, Sullivan PA. The production and growth characteristics of yeast and mycelial forms of Candida albicans in continuous culture. J Gen Microbiol. 1976;93:361–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Hida S, Miura NN, Adachi Y, Ohno N. Effect of Candida albicans cell wall glucan as adjuvant for induction of autoimmune arthritis in mice. J Autoimmun. 2005;25:93–101.PubMedCrossRefGoogle Scholar
  17. 17.
    Yi C, Cao Y, Mao SH, Liu H, Ji LL, Xu SY, et al. Recombinant human growth hormone improves survival and protects against acute lung injury in murine Staphylococcus aureus sepsis. Inflamm Res. 2009;58:855–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Konrad FM, Reutershan J. CXCR2 in acute lung injury. Mediators Inflamm. 2012;2012:740987.PubMedCrossRefGoogle Scholar
  19. 19.
    Rollins BJ. Chemokines. Blood. 1997;90:909–28.PubMedGoogle Scholar
  20. 20.
    Tekamp-Olson P, Gallegos C, Bauer D, McClain J, Sherry B, Fabre M, et al. Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues. J Exp Med. 1990;172:911–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee J, Cacalano G, Camerato T, Toy K, Moore MW, Wood WI. Chemokine binding and activities mediated by the mouse IL-8 receptor. J Immunol. 1995;155:2158–64.PubMedGoogle Scholar
  22. 22.
    Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8:31–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A, et al. Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity. 2010;32:681–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22:507–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Slack EC, Robinson MJ, Hernanz-Falcon P, Brown GD, Williams DL, Schweighoffer E, et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur J Immunol. 2007;37:1600–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Steele C, Rapaka RR, Metz A, Pop SM, Williams DL, Gordon S, et al. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 2005;1:e42.PubMedCrossRefGoogle Scholar
  27. 27.
    Thornton BP, Vetvicka V, Pitman M, Goldman RC, Ross GD. Analysis of the sugar specificity and molecular location of the beta-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J Immunol. 1996;156:1235–46.PubMedGoogle Scholar
  28. 28.
    Sato T, Iwabuchi K, Nagaoka I, Adachi Y, Ohno N, Tamura H, et al. Induction of human neutrophil chemotaxis by Candida albicans-derived beta-1,6-long glycoside side-chain-branched beta-glucan. J Leukoc Biol. 2006;80:204–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Van Ziffle JA, Lowell CA. Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection. Blood. 2009;114:4871–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol. 2008;6:67–78.PubMedCrossRefGoogle Scholar
  31. 31.
    Farnand AW, Eastman AJ, Herrero R, Hanson JF, Mongovin S, Altemeier WA, et al. Fas activation in alveolar epithelial cells induces KC (CXCL1) release by a MyD88-dependent mechanism. Am J Respir Cell Mol Biol. 2011;45:650–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Sharma AK, Fernandez LG, Awad AS, Kron IL, Laubach VE. Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-alpha during pulmonary ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2007;293:L105–13.PubMedCrossRefGoogle Scholar
  33. 33.
    Ortiz LA, Lasky J, Hamilton RF Jr, Holian A, Hoyle GW, Banks W, et al. Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp Lung Res. 1998;24:721–43.PubMedCrossRefGoogle Scholar
  34. 34.
    Piguet PF, Collart MA, Grau GE, Sappino AP, Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990;344:245–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Ramos CD, Fernandes KS, Canetti C, Teixeira MM, Silva JS, Cunha FQ. Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1alpha, TNF-alpha and LTB(4). Eur J Immunol. 2006;36:2025–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Mizuki Homme
    • 1
  • Nao Tateno
    • 1
  • Noriko Miura
    • 2
  • Naohito Ohno
    • 2
  • Yasuaki Aratani
    • 1
  1. 1.Graduate School of NanobioscienceYokohama City UniversityKanazawa, YokohamaJapan
  2. 2.Laboratory for Immunopharmacology of Microbial Products, School of PharmacyTokyo University of Pharmacy and Life SciencesHachiojiJapan

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