Regulation of lung autophagy by proteinase-activated receptor 2 activation

Lungs from patients with chronic obstructive pulmonary disease (COPD) display hallmarks of premature ageing, including dysregulated autophagy, leading to cellular senescence. The underlying mechanisms remain unclear. Proteinase activated receptor 2 (PAR2) is a potential therapeutic target for inflammatory conditions, with documented roles in lung pathology. A role for this receptor in lung ageing is yet unexplored.

Autophagic markers LC3 and ATG7 were examined in C57BL/6 wild type and PAR2-/- knock out lung tissue using immunohistochemistry. Autophagic flux was quantified through Marfluorescent imaging (CYTO-ID detection kit) in human bronchial epithelial cell line BEAS-2B and primary human bronchial epithelial cells from healthy (HBEC) and COPD patient donors (DHBEC), after PAR2 stimulation with SLIGKV agonist (cf. VKGILS control).

ATG7 (plt;0.005) and LC3 (plt;0.05) positive cells were significantly upregulated in PAR2-deficient lungs (Figure 1). PAR2 was present on epithelial cultures, with redistribution upon stimulation. PAR2 stimulation in BEAS-2B resulted in a significant reduction of autophagic vesicles cf. VKGILS (plt;0.001). Whilst similar behaviour was observed in HBEC, DHBEC exhibited autophagic flux dysregulation.

This study provides the first data describing a role for PAR2 in the regulation of autophagy in airway epithelia, suggesting a potential mechanism that may underpin premature lung ageing in conditions such as COPD.