Chaperone-mediated autophagy supports organ regeneration and fibroblast quiescence in mouse models of fibrosis.

Abstract

The core of organ fibrosis formation lies in the regenerative defects of parenchymal cells and in the excessive activation of fibroblasts, yet methods to simultaneously address these pathological cell types remain lacking. Here, we found that the expression of the chaperone-mediated autophagy (CMA) limiting factor lysosome-associated membrane protein type 2A (LAMP2A) was consistently down-regulated in mouse models of bleomycin-induced pulmonary fibrosis, carbon tetrachloride (CCl₄)-induced liver fibrosis, and folic acid-induced renal fibrosis. We also confirmed a low CMA score in patients with idiopathic pulmonary fibrosis, renal fibrosis, systemic sclerosis, and myocardial fibrosis. In the three mouse models, recombinant adeno-associated virus-mediated overexpression of <i>Lamp2a</i> was sufficient to inhibit the initiation and progression of fibrosis. Mechanistically, we demonstrated that LAMP2A overexpression in cultured fibroblast cell lines and each of the three mouse models could suppress fibroblast activation and reverse established myofibroblast fates by directly degrading the mechanosensitive protein integrin subunit beta 1. In addition, through cell type-specific <i>Lamp2a</i> overexpression in these fibrotic mouse models, we found that LAMP2A could promote regeneration in the liver, lungs, and kidneys. Moreover, pharmacological activation of CMA in these mouse models also alleviated organ fibrosis and promoted functional recovery when fibrosis had already been established. Thus, our study identifies LAMP2A as a broad-spectrum antifibrotic factor and provides proof of principle for dual targeting of core fibrotic cells to treat fibrosis.