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 i...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708485 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dayanira Alsina‐Beauchamp |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-939e61b85a3b4a58b2f2dc2991a14ffb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-939e61b85a3b4a58b2f2dc2991a14ffb2025-08-20T04:03:07ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-04-0110511510.15252/emmm.201708485Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunityDayanira Alsina‐Beauchamp0Alejandra Escós1Pilar Fajardo2Diego González‐Romero3Ester Díaz‐Mora4Ana Risco5Miguel A Martín‐Serrano6Carlos del Fresno7Jorge Dominguez‐Andrés8Noelia Aparicio9Rafal Zur10Natalia Shpiro11Gordon D Brown12Carlos Ardavín13Mihai G Netea14Susana Alemany15Juan J Sanz‐Ezquerro16Ana Cuenda17Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICImmunobiology of Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos IIIDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICMedical Research Council Protein Phosphorylation Unit, Sir James Black Building, School of Life Sciences, University of DundeeAberdeen Fungal Group, Institute of Medical Sciences, Medical Research Council Centre for Medical Mycology at the University of AberdeenDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical CentreInstituto de Investigaciones Biomédicas Alberto Sols, CSIC‐UAMDepartment of Cellular and Molecular Biology, CNB/CSICDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSICAbstract 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.https://doi.org/10.15252/emmm.201708485Candida albicansinfectionkinase inhibitorp38MAPKsignalling |
| spellingShingle | 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 Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity EMBO Molecular Medicine Candida albicans infection kinase inhibitor p38MAPK signalling |
| title | Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity |
| title_full | Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity |
| title_fullStr | Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity |
| title_full_unstemmed | Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity |
| title_short | Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity |
| title_sort | myeloid cell deficiency of p38γ p38δ protects against candidiasis and regulates antifungal immunity |
| topic | Candida albicans infection kinase inhibitor p38MAPK signalling |
| url | https://doi.org/10.15252/emmm.201708485 |
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