Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

Dayanira Alsina-Beauchamp, Alejandra Escós, Pilar Fajardo, Diego González-Romero, Ester Díaz-Mora, Ana Risco, Miguel A. Martín-Serrano, Carlos del Fresno, Jorge Dominguez-Andrés, Noelia Aparicio, Rafal Zur, Natalia Shpiro, Gordon D. Brown, Carlos Ardavín, Mihai G. Netea, Susana Alemany, Juan J. Sanz-Ezquerro, Ana Cuenda

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Abstract

Candida albicans is a frequent etiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38J and p38G regulate the innate immune response to C. albicans. We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38J/p38G. In mice, p38J/p38G deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper-inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38J/G null mice, reducing septic shock. p38J/p38G in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38J/p38G in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
Original languageEnglish
Article numbere8485
JournalEMBO Molecular Medicine
Volume10
Issue number5
Early online date16 Apr 2018
DOIs
Publication statusPublished - May 2018

Keywords

  • p38MAPK
  • signalling
  • infection
  • Candida albicans
  • Kinase inhibitor

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    Alsina-Beauchamp, D., Escós, A., Fajardo, P., González-Romero, D., Díaz-Mora, E., Risco, A., Martín-Serrano, M. A., Fresno, C. D., Dominguez-Andrés, J., Aparicio, N., Zur, R., Shpiro, N., Brown, G. D., Ardavín, C., Netea, M. G., Alemany, S., Sanz-Ezquerro, J. J., & Cuenda, A. (2018). Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. EMBO Molecular Medicine, 10(5), [e8485]. https://doi.org/10.15252/emmm.201708485