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Myeloid cell deficiency of p38?/p38? 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 p38? and p38? 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 p38?/p38?. In mice, p38?/p38? 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 p38?/?-null mice, reducing septic shock. p38?/p38? in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38?/p38? in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.

SUBMITTER: Alsina-Beauchamp D

PROVIDER: S-EPMC5938613 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity.

Alsina-Beauchamp Dayanira D Escós Alejandra A Fajardo Pilar P González-Romero Diego D Díaz-Mora Ester E Risco Ana A Martín-Serrano Miguel A MA Del Fresno Carlos C Dominguez-Andrés Jorge J Aparicio Noelia N Zur Rafal R Shpiro Natalia N Brown Gordon D GD Ardavín Carlos C Netea Mihai G MG Alemany Susana S Sanz-Ezquerro Juan J JJ Cuenda Ana A

EMBO molecular medicine 20180501 5

<i>Candida albicans</i> 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 <i>C. albicans</i> 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 ...[more]

PMID: 29661910

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Project description:Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

Dataset Information

Myeloid cell deficiency of p38?/p38? protects against candidiasis and regulates antifungal immunity.

Publications

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity.

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