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Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium
Zhi-Hua Chen1, Yin-Fang Wu1, Ping-Li Wang1
1a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
Abstract:
Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.
Insights
Autophagy plays a key role in airway injury from environmental particulate matter (PM). Blocking autophagy reduces inflammation and mucus production, suggesting therapeutic potential for PM-induced respiratory conditions.
Area of Science:
- Cellular Biology
- Environmental Health
- Respiratory Medicine
Background:
- Environmental ultrafine particulate matter (PM) causes airway injury through unclear molecular pathways.
- Autophagy, a cellular degradation process, is implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of autophagy in regulating inflammation and mucus hyperproduction induced by PM.
- To explore the therapeutic potential of modulating autophagy in PM-induced airway diseases.
Main Methods:
- Utilized human bronchial epithelial (HBE) cells and mouse models exposed to PM.
- Employed genetic knockdown of autophagy-related genes (Becn1, Lc3b) and lysosomal inhibition.
- Assessed inflammatory cytokine (IL-8, IL-6) and MUC5AC expression, and airway inflammation in vivo.
Main Results:
- PM exposure triggered autophagy in HBE cells, with particle engulfment by autophagosomes.
- Genetic blockade of autophagy significantly reduced PM-induced IL-8, IL-6, and MUC5AC expression in HBE cells.
- Impaired autophagy in mice led to reduced airway inflammation and mucus hyperproduction following PM exposure.
- Lysosomal inhibition aggravated IL-8 production via NFKB1 but attenuated MUC5AC expression via AP-1.
Conclusions:
- Autophagy is essential for PM-induced airway epithelial injury.
- Inhibition of autophagy demonstrates therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction.
- The autophagic flux differentially regulates inflammatory and mucus production pathways.
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