Myeloid cell deficiency of p38 gamma/p38 delta protects against candidiasis and regulates antifungal immunity
SourceEMBO Molecular Medicine, 10, 5, (2018)
Article / Letter to editor
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EMBO Molecular Medicine
SubjectAll institutes and research themes of the Radboud University Medical Center; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
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 p38gamma and p38delta 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 p38gamma/p38delta. In mice, p38gamma/p38delta 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 p38gamma/delta-null mice, reducing septic shock. p38gamma/p38delta in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38gamma/p38delta in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
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