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 (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Candida albicans is a frequent aetiologic 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 p38γ and p38δ 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 p38γ/p38δ. In mice, p38γ/p38δ 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 p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.

Original languageEnglish
Article numbere8485
Pages (from-to)1-15
Number of pages15
JournalEmbo Molecular Medicine
Volume10
Issue number5
Early online date16 Apr 2018
DOIs
Publication statusPublished - 1 May 2018

Fingerprint

Candidiasis
Myeloid Cells
Candida albicans
Immunity
Macrophages
MAP Kinase Signaling System
Immunocompromised Host
Septic Shock
Infection
Innate Immunity
Sepsis
Neutrophils
Leukocytes
Pharmacology
Inflammation
Kidney
Mortality
Therapeutics
Pharmaceutical Preparations

Keywords

  • Candida albicans
  • infection
  • kinase inhibitor
  • p38MAPK
  • signalling

Cite this

Alsina-Beauchamp, D., Escós, A., Fajardo, P., González-Romero, D., Díaz-Mora, E., Risco, A., ... Cuenda, A. (2018). Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. Embo Molecular Medicine, 10(5), 1-15. [e8485]. https://doi.org/10.15252/emmm.201708485
Alsina-Beauchamp, Dayanira ; Escós, Alejandra ; Fajardo, Pilar ; González-Romero, Diego ; Díaz-Mora, Ester ; Risco, Ana ; Martín-Serrano, Miguel A. ; Del Fresno, Carlos ; Dominguez-Andrés, Jorge ; Aparicio, Noelia ; Zur, Rafal ; Shpiro, Natalia ; Brown, Gordon D. ; Ardavín, Carlos ; Netea, Mihai G. ; Alemany, Susana ; Sanz-Ezquerro, Juan J. ; Cuenda, Ana. / Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. In: Embo Molecular Medicine. 2018 ; Vol. 10, No. 5. pp. 1-15.
@article{f4e75b6742314f0ea079ccda52fe2666,
title = "Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity",
abstract = "Candida albicans is a frequent aetiologic 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 p38γ and p38δ 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 p38γ/p38δ. In mice, p38γ/p38δ 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 p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.",
keywords = "Candida albicans, infection, kinase inhibitor, p38MAPK, signalling",
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 {Del Fresno}, Carlos 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 = "We thank P. Cohen for critically reading the manuscript. This work was supported by grants from the MINECO [SAF2013-45331-R and SAF2016-79792- R (AEI/FEDER, UE)] to AC and JJS-E, La Marat{\'o} TV3 Foundation (20133431) to AC and (SAF2014-52009-R) to SA. ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research to MGN, and Wellcome Trust, the Medical Research Council (MRC; UK), the MRC Centre for Medical Mycology at the University of Aberdeen to GDB. DAB and AE The paper explained Problem Candida infections cause high mortality in immunocompromised patients. Sepsis caused by C. albicans is one of the most frequent in hospital intensive care units in patients with AIDS or auto-immune diseases and in those undergoing anti-cancer chemotherapy or organ transplantation. Recent studies have shown the important roles of p38c and p38d (p38c/p38d) in regulating cytokine production, T-cell activation or immune cell recruitment in arthritis and colitis, and in tumorigenesis associated with inflammation. While several studies have demonstrated that p38c/p38d are involved in inflammatory processes, the role of these kinases in C. albicans infection is completely unknown. Therefore, we hypothesized that p38c/p38d might regulate disseminated candidiasis. Results We show that p38c/p38d control cytokine production in response to C. albicans in macrophages (mediated by Dectin-1 and TLR receptors) and describe a novel signalling pathway downstream of Dectin-1, which is regulated by p38c/p38d. Furthermore, using a mouse model of systemic candidiasis, we found that the deletion of p38c/p38d in myeloid cells protected against C. albicans infection. Mechanistically, we found that p38c/p38d deletion increased antifungal killing capacity of neutrophils and macrophages mediated by increased NOS expression and ROS production in these phagocytes. In addition, p38c/p38d deficiency decreased macrophage and neutrophil recruitment to infected kidneys and reduced the production of cytokines and chemokines. We also demonstrate that chemical inhibition of p38c/p38d in vivo exerts antifungal therapeutic effects in mice infected with C. albicans. Impact Our findings define a major role for p38c/p38d in C. albicans infection and underscore their importance in regulating inflammatory processes. Our observations point out p38c/p38d as potential targets for the development of novel antifungal drugs for human disease and suggest that therapies aimed to inhibit p38c/p38d might significantly reduce candidiasis. ª 2018 The Authors EMBO Molecular Medicine e8485 | 2018 13 of 15 Dayanira Alsina-Beauchamp et al p38c/p38d regulate C. albicans infection EMBO Molecular Medicine Published online: April 16, 2018 receive MINECO FPI fellowships, AR a MINECO Juan de la Cierva award and JD-A a La Caixa Foundation PhD fellowship",
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Alsina-Beauchamp, D, Escós, A, Fajardo, P, González-Romero, D, Díaz-Mora, E, Risco, A, Martín-Serrano, MA, Del Fresno, C, 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, pp. 1-15. https://doi.org/10.15252/emmm.201708485

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. / Alsina-Beauchamp, Dayanira; Escós, Alejandra; Fajardo, Pilar; González-Romero, Diego; Díaz-Mora, Ester; Risco, Ana; Martín-Serrano, Miguel A.; Del Fresno, Carlos; Dominguez-Andrés, Jorge; Aparicio, Noelia; Zur, Rafal; Shpiro, Natalia; Brown, Gordon D.; Ardavín, Carlos; Netea, Mihai G.; Alemany, Susana; Sanz-Ezquerro, Juan J.; Cuenda, Ana (Lead / Corresponding author).

In: Embo Molecular Medicine, Vol. 10, No. 5, e8485, 01.05.2018, p. 1-15.

Research output: Contribution to journalArticle

TY - JOUR

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 - Del Fresno, Carlos

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 - We thank P. Cohen for critically reading the manuscript. This work was supported by grants from the MINECO [SAF2013-45331-R and SAF2016-79792- R (AEI/FEDER, UE)] to AC and JJS-E, La Marató TV3 Foundation (20133431) to AC and (SAF2014-52009-R) to SA. ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research to MGN, and Wellcome Trust, the Medical Research Council (MRC; UK), the MRC Centre for Medical Mycology at the University of Aberdeen to GDB. DAB and AE The paper explained Problem Candida infections cause high mortality in immunocompromised patients. Sepsis caused by C. albicans is one of the most frequent in hospital intensive care units in patients with AIDS or auto-immune diseases and in those undergoing anti-cancer chemotherapy or organ transplantation. Recent studies have shown the important roles of p38c and p38d (p38c/p38d) in regulating cytokine production, T-cell activation or immune cell recruitment in arthritis and colitis, and in tumorigenesis associated with inflammation. While several studies have demonstrated that p38c/p38d are involved in inflammatory processes, the role of these kinases in C. albicans infection is completely unknown. Therefore, we hypothesized that p38c/p38d might regulate disseminated candidiasis. Results We show that p38c/p38d control cytokine production in response to C. albicans in macrophages (mediated by Dectin-1 and TLR receptors) and describe a novel signalling pathway downstream of Dectin-1, which is regulated by p38c/p38d. Furthermore, using a mouse model of systemic candidiasis, we found that the deletion of p38c/p38d in myeloid cells protected against C. albicans infection. Mechanistically, we found that p38c/p38d deletion increased antifungal killing capacity of neutrophils and macrophages mediated by increased NOS expression and ROS production in these phagocytes. In addition, p38c/p38d deficiency decreased macrophage and neutrophil recruitment to infected kidneys and reduced the production of cytokines and chemokines. We also demonstrate that chemical inhibition of p38c/p38d in vivo exerts antifungal therapeutic effects in mice infected with C. albicans. Impact Our findings define a major role for p38c/p38d in C. albicans infection and underscore their importance in regulating inflammatory processes. Our observations point out p38c/p38d as potential targets for the development of novel antifungal drugs for human disease and suggest that therapies aimed to inhibit p38c/p38d might significantly reduce candidiasis. ª 2018 The Authors EMBO Molecular Medicine e8485 | 2018 13 of 15 Dayanira Alsina-Beauchamp et al p38c/p38d regulate C. albicans infection EMBO Molecular Medicine Published online: April 16, 2018 receive MINECO FPI fellowships, AR a MINECO Juan de la Cierva award and JD-A a La Caixa Foundation PhD fellowship

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Candida albicans is a frequent aetiologic 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 p38γ and p38δ 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 p38γ/p38δ. In mice, p38γ/p38δ 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 p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ 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 aetiologic 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 p38γ and p38δ 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 p38γ/p38δ. In mice, p38γ/p38δ 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 p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.

KW - Candida albicans

KW - infection

KW - kinase inhibitor

KW - p38MAPK

KW - signalling

U2 - 10.15252/emmm.201708485

DO - 10.15252/emmm.201708485

M3 - Article

VL - 10

SP - 1

EP - 15

JO - Embo Molecular Medicine

JF - Embo Molecular Medicine

SN - 1757-4676

IS - 5

M1 - e8485

ER -

Alsina-Beauchamp D, Escós A, Fajardo P, González-Romero D, Díaz-Mora E, Risco A et al. Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. Embo Molecular Medicine. 2018 May 1;10(5):1-15. e8485. https://doi.org/10.15252/emmm.201708485