Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGFbeta signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S-/-) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfrbeta-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S-/- mice is primarily caused by defective Pdgfrbeta signaling. Here we show that LTBP4 induces Pdgfrbeta signaling by inhibiting the antioxidant Nrf2/Keap1 pathway in a TGFbeta-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair.
- Tomasovic, A.; Kurrle, N.; Wempe, F.; De-Zolt, S.; Scheibe, S.; Koli, K.; Serchinger, M.; Schnutgen, F.; Surun, D.; Sterner-Kock, A.; Weissmann, N.; von Melchner, H.
Keywords
- Copd
- Emphysema
- Ltbp4
- Nrf2
- Pdgfrbeta
- Ros
- Tgfbeta