Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity.
EMBO Mol Med
; 10(5)2018 05.
Article
em En
| MEDLINE
| ID: mdl-29661910
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.
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Base de dados:
MEDLINE
Assunto principal:
Candida albicans
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Candidíase
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Células Mieloides
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Proteína Quinase 12 Ativada por Mitógeno
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Proteína Quinase 13 Ativada por Mitógeno
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article