Susceptibility of LC3B Knockout Mice to Lung Injury and Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease with a remarkable age-related onset which may be triggered by chronic lung alveolar epithelial cell type II (AECII) injury and apoptosis. AECII are classical secretory cells which contain lamellar bodies that are lysosome related organelles and are primarily responsible to store and secrete lung surfactant. Recently, the principle role of autophagy, a lysosome dependent protein quality control mechanism has been studied in the development of lung fibrosis, both in humans as well as in animal models. Yeast Atg8 or mammalian microtubule-associated protein 1 light chain 3 beta (MAP1LC3B/LC3B) is an important autophagy related protein and its lipidated form, LC3BII is a reliable marker of the autophagosomes. In this study, we aim to decipher the involvement of this protein in the development of lung fibrosis. A systematic analysis of the LC3B−/− mice lungs revealed that aged LC3B−/− mice showed increased cellularity, smaller lamellar body profiles, increased apoptosis of AECII paralleled with surfactant alterations, increased lysosomal and endoplasmic reticulum stress providing clues on the importance of this distal autophagy protein in lung fibrosis development. Further, in vitro knockdown of LC3B sensitized mouse lung epithelial cells to bleomycin induced apoptosis. In vivo, LC3B−/− mice displayed increased susceptibility to bleomycin induced lung injury and fibrosis. We conclude that LC3B plays essential roles in AECII and protects the alveolar epithelial cells from bleomycin induced lung injury and fibrosis.