Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.
Pamela P LeeDamián Lobato-MárquezNayani PramanikAndrea SirianniVanessa Daza-CajigalElizabeth RiversAlessia CavazzaGerben BoumaDale MouldingKjell HultenbyLisa S WesterbergMichael HollinsheadYu-Lung LauSiobhan O BurnsSerge MostowyMona Bajaj-ElliottAdrian J ThrasherPublished in: Nature communications (2017)
Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.
Keyphrases
- cell death
- oxidative stress
- dendritic cells
- immune response
- signaling pathway
- endoplasmic reticulum stress
- escherichia coli
- cell cycle arrest
- end stage renal disease
- randomized controlled trial
- ejection fraction
- newly diagnosed
- chronic kidney disease
- case report
- protein protein
- replacement therapy
- binding protein
- risk assessment
- weight gain
- cystic fibrosis
- smoking cessation
- human health
- candida albicans
- weight loss
- klebsiella pneumoniae
- regulatory t cells
- liquid chromatography