Salt Inducible Kinase 2 regulates fibrosis during bleomycin-induced lung injury

van Gijsel-Bonnello, M. et al. (2022) Salt Inducible Kinase 2 regulates fibrosis during bleomycin-induced lung injury. Journal of Biological Chemistry, 298(12), 102644. (doi: 10.1016/j.jbc.2022.102644) (PMID:36309093) (PMCID:PMC9706632)

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and normally fatal disease with limited treatment options. The tyrosine kinase inhibitor Nintedanib has recently been approved for the treatment of IPF, and its effectiveness has been linked to its ability to inhibit a number of receptor tyrosine kinases including the platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor receptors. We show here that Nintedanib also inhibits Salt Inducible Kinase 2 (SIK2), with a similar IC50 to its reported tyrosine kinase targets. Nintedanib also inhibited the related kinases SIK1 and SIK3, although with 12- and 72-fold higher IC50s, respectively. To investigate if the inhibition of SIK2 may contribute to the effectiveness of Nintedanib in treating lung fibrosis, mice with kinase-inactive knockin mutations were tested using a model of bleomycin-induced lung fibrosis. We found that loss of SIK2 activity protects against bleomycin-induced fibrosis, as judged by collagen deposition and histological scoring. Loss of both SIK1 and SIK2 activity had a similar effect to loss of SIK2 activity. Total SIK3 knockout mice have a developmental phenotype making them unsuitable for analysis in this model; however, we determined that conditional knockout of SIK3 in the immune system did not affect bleomycin-induced lung fibrosis. Together, these results suggest that SIK2 is a potential drug target for the treatment of lung fibrosis.

• Item Type: Articles
• Additional Information: This work was supported by the Medical Research Council UK (MR/R021406/1) and Versus Arthritis (21425 and 20623).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kurowska-Stolarska, Professor Mariola and Marchesi, Dr Francesco
• Authors: van Gijsel-Bonnello, M., Darling, N. J., Tanaka, T., Di Carmine, S., Marchesi, F., Thomson, S., Clark, K., Kurowska-Stolarska, M., McSorley, H. J., Cohen, P., and Arthur, J. S. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Journal of Biological Chemistry
• Publisher: Elsevier
• ISSN: 0021-9258
• ISSN (Online): 1083-351X
• Published Online: 26 October 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Biological Chemistry 298(12): 102644
• Publisher Policy: Reproduced under a Creative Commons License