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

doi:10.15252/emmm.201708485

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

Applied Medicine

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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 language	English
Article number	e8485
Journal	EMBO Molecular Medicine
Volume	10
Issue number	5
Early online date	16 Apr 2018
DOIs	https://doi.org/10.15252/emmm.201708485
Publication status	Published - May 2018

Bibliographical note

Fundació la Marató de TV3 (GrantNumber(s): 20133431; Grant recipient(s): Ana Cuenda)
Wellcome Trust (GrantNumber(s): 97377, 102705; Grant recipient(s): GORDON D. BROWN)
Ministerio de Economía y Competitividad (GrantNumber(s): SAF2016-79792-R, SAF2014- 52009-R, SAF2013-45331-R; Grant recipient(s): Ana Cuenda, SUSANA ALEMANY)
Medical Research Council (GrantNumber(s): MR/N006364/1; Grant recipient(s): GORDON D. BROWN)
ERC Consolidator Grant (GrantNumber(s): 310372; Grant recipient(s): Mihai Netea)

Keywords

p38MAPK
signalling
infection
Candida albicans
Kinase inhibitor

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10.15252/emmm.201708485Licence: CC BY

Myeloid cell deficiency of p38γp38δ protects against candidiasis and regulates antifungal immunity
© 2018 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.1 MBLicence: CC BY

Cite this

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), Article e8485. https://doi.org/10.15252/emmm.201708485

Alsina-Beauchamp, D, Escós, A, Fajardo, P, González-Romero, D, Díaz-Mora, E, Risco, A, Martín-Serrano, MA, Fresno, CD, Dominguez-Andrés, J, Aparicio, N, Zur, R, Shpiro, N, Brown, GD, Ardavín, C, Netea, MG, Alemany, S, Sanz-Ezquerro, JJ & Cuenda, A 2018, 'Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity', EMBO Molecular Medicine, vol. 10, no. 5, e8485. https://doi.org/10.15252/emmm.201708485

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title = "Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity",

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. ",

keywords = "p38MAPK, signalling, infection, Candida albicans, Kinase inhibitor",

author = "Dayanira Alsina-Beauchamp and Alejandra Esc{\'o}s and Pilar Fajardo and Diego Gonz{\'a}lez-Romero and Ester D{\'i}az-Mora and Ana Risco and Mart{\'i}n-Serrano, {Miguel A.} and Fresno, {Carlos del} and Jorge Dominguez-Andr{\'e}s and Noelia Aparicio and Rafal Zur and Natalia Shpiro and Brown, {Gordon D.} and Carlos Ardav{\'i}n and Netea, {Mihai G.} and Susana Alemany and Sanz-Ezquerro, {Juan J.} and Ana Cuenda",

note = "Fundaci{\'o} la Marat{\'o} de TV3 (GrantNumber(s): 20133431; Grant recipient(s): Ana Cuenda) Wellcome Trust (GrantNumber(s): 97377, 102705; Grant recipient(s): GORDON D. BROWN) Ministerio de Econom{\'i}a y Competitividad (GrantNumber(s): SAF2016-79792-R, SAF2014- 52009-R, SAF2013-45331-R; Grant recipient(s): Ana Cuenda, SUSANA ALEMANY) Medical Research Council (GrantNumber(s): MR/N006364/1; Grant recipient(s): GORDON D. BROWN) ERC Consolidator Grant (GrantNumber(s): 310372; Grant recipient(s): Mihai Netea)",

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doi = "10.15252/emmm.201708485",

language = "English",

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journal = "EMBO Molecular Medicine",

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T1 - Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

AU - Alsina-Beauchamp, Dayanira

AU - Escós, Alejandra

AU - Fajardo, Pilar

AU - González-Romero, Diego

AU - Díaz-Mora, Ester

AU - Risco, Ana

AU - Martín-Serrano, Miguel A.

AU - Fresno, Carlos del

AU - Dominguez-Andrés, Jorge

AU - Aparicio, Noelia

AU - Zur, Rafal

AU - Shpiro, Natalia

AU - Brown, Gordon D.

AU - Ardavín, Carlos

AU - Netea, Mihai G.

AU - Alemany, Susana

AU - Sanz-Ezquerro, Juan J.

AU - Cuenda, Ana

N1 - Fundació la Marató de TV3 (GrantNumber(s): 20133431; Grant recipient(s): Ana Cuenda) Wellcome Trust (GrantNumber(s): 97377, 102705; Grant recipient(s): GORDON D. BROWN) Ministerio de Economía y Competitividad (GrantNumber(s): SAF2016-79792-R, SAF2014- 52009-R, SAF2013-45331-R; Grant recipient(s): Ana Cuenda, SUSANA ALEMANY) Medical Research Council (GrantNumber(s): MR/N006364/1; Grant recipient(s): GORDON D. BROWN) ERC Consolidator Grant (GrantNumber(s): 310372; Grant recipient(s): Mihai Netea)

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - p38MAPK

KW - signalling

KW - infection

KW - Candida albicans

KW - Kinase inhibitor

U2 - 10.15252/emmm.201708485

DO - 10.15252/emmm.201708485

M3 - Article

SN - 1757-4684

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 5

M1 - e8485

ER -

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

Abstract

Bibliographical note

Keywords

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