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Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages
Jenny M Tam1, Michael K Mansour1, Nida S Khan2
1Department of Medicine, Division of Infectious Diseases Department of Medicine, Harvard Medical School, Boston.
Abstract:
Autophagy has been postulated to play role in mammalian host defense against fungal pathogens, although the molecular details remain unclear. Here, we show that primary macrophages deficient in the autophagic factor LC3 demonstrate diminished fungicidal activity but increased cytokine production in response to Candida albicans stimulation. LC3 recruitment to fungal phagosomes requires activation of the fungal pattern receptor dectin-1. LC3 recruitment to the phagosome also requires Syk signaling but is independent of all activity by Toll-like receptors and does not require the presence of the adaptor protein Card9. We further demonstrate that reactive oxygen species generation by NADPH oxidase is required for LC3 recruitment to the fungal phagosome. These observations directly link LC3 to the inflammatory pathway against C. albicans in macrophages.
Insights
Autophagy, involving LC3, is crucial for macrophage defense against Candida albicans. Its recruitment to fungal phagosomes requires dectin-1, Syk signaling, and NADPH oxidase, impacting fungal clearance and inflammation.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Autophagy is implicated in host defense against fungal pathogens.
- The precise molecular mechanisms linking autophagy to fungal pathogen clearance remain incompletely understood.
Purpose of the Study:
- To elucidate the role of the autophagic factor LC3 in macrophage response to Candida albicans.
- To identify signaling pathways and molecular requirements for LC3 recruitment to fungal phagosomes.
Main Methods:
- Utilized primary macrophages deficient in LC3.
- Stimulated macrophages with Candida albicans.
- Assessed fungicidal activity and cytokine production.
- Investigated the involvement of dectin-1, Syk signaling, Toll-like receptors, Card9, and NADPH oxidase in LC3 recruitment.
Main Results:
- LC3-deficient macrophages exhibited reduced fungicidal activity and enhanced cytokine production against C. albicans.
- LC3 recruitment to fungal phagosomes was dependent on dectin-1 activation and Syk signaling.
- LC3 recruitment was independent of Toll-like receptors and Card9.
- NADPH oxidase-dependent reactive oxygen species generation was essential for LC3 recruitment.
Conclusions:
- LC3 plays a significant role in macrophage-mediated host defense against Candida albicans.
- The findings establish a direct link between LC3-mediated autophagy and the inflammatory response pathway against C. albicans in macrophages.