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The Critical Role of Notch1–TLR 4 Signaling in the Inflammatory and Fungicidal Activity of Macrophages Against Paracoccidioides brasiliensis Strain Pb18

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Abstract

Paracoccidioidomycosis is a systemic mycosis of deep nature that primarily affects the lung and can spread via lymphatic and hematogenous to other organs and tissues. It is mainly caused by Paracoccidioides brasiliensis fungus which exhibits thermal dimorphism. The innate immune system mediated by macrophages is extremely important for the control of infection and is involved in the induction and regulation of immune/inflammatory response. These cells are able to recognize pathogens through pattern recognition receptors (PRRs) such as Toll-like receptors (TLR). Beyond these PRRs, the importance of Notch signaling has recently been demonstrated in the innate immune system and the regulation of macrophage activity. Our data demonstrate that the Pb18 strain of P. brasiliensis is able to activate the transcription of Notch1 receptor in J774 macrophages. Activation of this receptor with also activation of TLR 4 (via LPS) induces IL-6 production, which favors the pathogenesis. By using a γ-secretase pharmacological inhibitor (DAPT) for inhibiting the activation of Notch1 receptor on macrophages, it is possible to observe the decreased fungal burden, less production of IL-6, and increased TNF-α and phagocytosis. Taken together, these results showed that Pb18 is able to induce the transcription of Notch1 receptor on macrophages and may provide a new immunity study approach in experimental paracoccidioidomycosis.

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References

  1. Gegembauer G, Araujo LM, Pereira EF, Rodrigues AM, Paniago AMM, Hahn RC, et al. Serology of paracoccidioidomycosis due to Paracoccidioides lutzii. PLoS Negl Trop Dis. 2014;8:e2986.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bocca AL, Amaral AC, Teixeira MM, Sato PK, Shikanai-Yasuda MA, Soares Felipe MS. Paracoccidioidomycosis: eco-epidemiology, taxonomy and clinical and therapeutic issues. Future Microbiol. 2013;8:1177–91.

    Article  PubMed  Google Scholar 

  3. Leopold Wager CM, Wormley FL. Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections. Mucosal Immunol. 2014;7:1023–35.

    Article  CAS  PubMed  Google Scholar 

  4. Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol. 2015;15:731–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13:1118–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.

    Article  CAS  PubMed  Google Scholar 

  7. Monsalve E, Pérez MA, Rubio A, Ruiz-Hidalgo MJ, Baladrón V, García-Ramírez JJ, et al. Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol. 2006;176:5362–73.

    Article  CAS  PubMed  Google Scholar 

  8. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76.

    Article  CAS  PubMed  Google Scholar 

  9. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Q, Wang C, Liu Z, Liu X, Han C, Cao X, et al. Notch signal suppresses Toll-like receptor-triggered inflammatory responses in macrophages by inhibiting extracellular signal-regulated kinase 1/2-mediated nuclear factor κB activation. J Biol Chem. 2012;287:6208–17.

    Article  CAS  PubMed  Google Scholar 

  11. Hertzog P. A notch in the toll belt. Immunity. 2008;29:663–5.

    Article  CAS  PubMed  Google Scholar 

  12. Hu X, Chung AY, Wu I, Foldi J, Chen J, Ji JD, et al. Integrated regulation of Toll-like receptor responses by Notch and interferon-γ pathways. Immunity. 2008;29:691–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Palaga T, Buranaruk C, Rengpipat S, Fauq AH, Golde TE, Kaufmann SHE, et al. Notch signaling is activated by TLR stimulation and regulates macrophage functions. Eur J Immunol. 2008;38:174–83.

    Article  CAS  PubMed  Google Scholar 

  14. Radtke F, MacDonald HR, Tacchini-Cottier F. Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol. 2013;13:427–37.

    Article  CAS  PubMed  Google Scholar 

  15. Maillard I, Adler SH, Pear WS. Notch and the immune system. Immunity. 2003;19:781–91.

    Article  CAS  PubMed  Google Scholar 

  16. Sangphech N, Osborne BA, Palaga T. Notch signaling regulates the phosphorylation of Akt and survival of lipopolysaccharide-activated macrophages via regulator of G protein signaling 19 (RGS19). Immunobiology. 2014;219:653–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maillard I, Fang T, Pear WS. Regulation of lymphoid development, differentiation, and function by the notch pathway. Annu Rev Immunol. 2005;23:945–74.

    Article  CAS  PubMed  Google Scholar 

  18. Wongchana W, Lawlor RG, Osborne BA, Palaga T. Impact of Notch1 deletion in macrophages on proinflammatory cytokine production and the outcome of experimental autoimmune encephalomyelitis. J Immunol. 2015;195:5337–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Radtke F, Fasnacht N, MacDonald HR. Notch signaling in the immune system. Immunity. 2010;32:14–27.

    Article  CAS  PubMed  Google Scholar 

  20. Ito T, Allen RM, Carson WF, Schaller M, Cavassani KA, Hogaboam CM, et al. The critical role of Notch ligand Delta-like 1 in the pathogenesis of influenza A virus (H1N1) infection. PLoS Pathog. 2011;7:e1002341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wongchana W, Palaga T. Direct regulation of interleukin-6 expression by Notch signaling in macrophages. Cell Mol Immunol. 2012;9:155–62.

    Article  CAS  PubMed  Google Scholar 

  22. Foldi J, Chung AY, Xu H, Zhu J, Outtz HH, Kitajewski J, et al. Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1. J Immunol. 2010;185:5023–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsao P-N, Wei S-C, Huang M-T, Lee M-C, Chou H-C, Chen C-Y, et al. Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response. J Biomed Sci. 2011;18:56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Marim FM, Silveira TN, Lima DS Jr, Zamboni DS. A method for generation of bone marrow derived macrophages from cryopreserved mouse bone marrow cells. Plos One. 2010;5(12):15263. doi:10.1371/journal.pone.0015263.

  25. Soares DA, de Andrade RV, Silva SS, Bocca AL, Felipe SA, Petrofeza S. Extracellular Paracoccidioides brasiliensis phospholipase B involvment in alveolar macrophage interaction. BMC Microbiol. 2010;10:241. doi:10.1186/1471-2180-10-241.

  26. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2004;4:11–24.

    Article  CAS  Google Scholar 

  27. Siqueira KZ, Campos Soares ÂMV, LA De D-M, Calvi SA, Peraçoli MTS. Interleukin-6 treatment enhances human monocyte permissiveness for Paracoccidioides brasiliensis growth by modulating cytokine production. Med Mycol. 2009;47:259–67.

    Article  CAS  PubMed  Google Scholar 

  28. Bermudez LE, Wu M, Petrofsky M, Young LS. Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immun. 1992;60:4245–52.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The present work was supported by FAPESP and Doctoral Fellowship from FAPESP (2012/14955-0).

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Authors and Affiliations

  1. Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Avenida Prof. Lineu Prestes, 580, Bloco 17, São Paulo, CEP: 05508-900, Brazil

    Lavínia Maria Dal’Mas Romera, Grasielle Pereira Jannuzzi, José Roberto Fogaça de Almeida & Sandro Rogério de Almeida

  2. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil

    Gilberto Hideo Kaihami

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  1. Lavínia Maria Dal’Mas Romera
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  2. Gilberto Hideo Kaihami
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Correspondence to Sandro Rogério de Almeida.

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Romera, L.M.D., Kaihami, G.H., Jannuzzi, G.P. et al. The Critical Role of Notch1–TLR 4 Signaling in the Inflammatory and Fungicidal Activity of Macrophages Against Paracoccidioides brasiliensis Strain Pb18. Mycopathologia 182, 797–807 (2017). https://doi.org/10.1007/s11046-017-0154-4

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  • DOI: https://doi.org/10.1007/s11046-017-0154-4

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