Impaired phagocytosis directs human monocyte activation in response to fungal derived β-glucan particles

Eur J Immunol. 2018 May;48(5):757-770. doi: 10.1002/eji.201747224. Epub 2018 Feb 5.

Abstract

Recognition of the fungal cell wall carbohydrate β-glucan by the host receptor Dectin-1 elicits broad immunomodulatory responses, such as phagocytosis and activation of oxidative burst. These responses are essential for engulfing and killing fungal pathogens. Phagocytic monocytes are key mediators of these early host inflammatory responses to infection. Remarkably, whether phagocytosis of fungal β-glucan leads to an inflammatory response in human monocytes remains to be established. Here, we show that phagocytosis of heat-killed Candida albicans is essential to trigger inflammation and cytokine release. By contrast, inhibition of actin-dependent phagocytosis of particulate (1-3,1-6)-β-glucan induces a strong inflammatory signature. Sustained monocyte activation, induced by fungal β-glucan particles upon actin cytoskeleton disruption, relies on Dectin-1 and results in the classical caspase-1 inflammasome formation through NLRP3, generation of an oxidative burst, NF-κB activation, and increased inflammatory cytokine release. PI3K and NADPH oxidase were crucial for both cytokine secretion and ROS generation, whereas Syk signaling mediated only cytokine production. Our results highlight the mechanism by which phagocytosis tightly controls the activation of phagocytes by fungal pathogens and strongly suggest that actin cytoskeleton dynamics are an essential determinant of the host's susceptibility or resistance to invasive fungal infections.

Keywords: Fungi; Inflammation; Monocytes; Phagocytosis; β-glucan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Candida albicans / immunology*
  • Candidiasis / immunology*
  • Cells, Cultured
  • Cytokines / metabolism
  • Fungal Polysaccharides / immunology*
  • Humans
  • Lectins, C-Type / metabolism
  • Leukocytes, Mononuclear / immunology*
  • NADPH Oxidases / metabolism
  • NF-kappa B / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Phagocytes / immunology
  • Phagocytes / metabolism
  • Phagocytosis / immunology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Respiratory Burst / immunology
  • beta-Glucans / immunology*

Substances

  • CLEC7A protein, human
  • Cytokines
  • Fungal Polysaccharides
  • Lectins, C-Type
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • beta-Glucans
  • NADPH Oxidases