Open AccessMyeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
Author(s) -
AlsinaBeauchamp Dayanira,
Escós Alejandra,
Fajardo Pilar,
GonzálezRomero Diego,
DíazMora Ester,
Risco Ana,
MartínSerrano Miguel A,
Fresno Carlos,
DominguezAndrés Jorge,
Aparicio Noelia,
Zur Rafal,
Shpiro Natalia,
Brown Gordon D,
Ardavín Carlos,
Netea Mihai G,
Alemany Susana,
SanzEzquerro Juan J,
Cuenda Ana
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708485
Subject(s) - medicine , library science , clinical immunology , antifungal , immunology , humanities , art , allergy , dermatology , computer science
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 TAK 1‐ TPL 2‐ MKK 1‐ ERK 1/2 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 p38 MAPK s may be therapeutic targets for treating C. albicans infection in humans.