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

EMBO Mol Med. 2018 May;10(5):e8485. doi: 10.15252/emmm.201708485.

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.

Keywords: Candida albicans; infection; kinase inhibitor; p38MAPK; signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Candida albicans / immunology*
  • Candida albicans / physiology
  • Candidiasis / genetics
  • Candidiasis / immunology*
  • Candidiasis / microbiology
  • Female
  • Host-Pathogen Interactions / immunology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 12 / deficiency
  • Mitogen-Activated Protein Kinase 12 / genetics
  • Mitogen-Activated Protein Kinase 12 / immunology*
  • Mitogen-Activated Protein Kinase 13 / deficiency
  • Mitogen-Activated Protein Kinase 13 / genetics
  • Mitogen-Activated Protein Kinase 13 / immunology*
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / microbiology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / microbiology
  • Nitric Oxide Synthase Type II / immunology
  • Nitric Oxide Synthase Type II / metabolism
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Reactive Oxygen Species
  • Nitric Oxide Synthase Type II
  • Mitogen-Activated Protein Kinase 12
  • Mitogen-Activated Protein Kinase 13