Inhibition of the MER tyrosine kinase ameliorates pulmonary fibrosis by suppressing macrophage M2 polarisation and osteopontin signalling

BACKGROUND AND PURPOSE: The MER proto-oncogene tyrosine kinase (MERTK) has been implicated in the pathogenesis of pulmonary fibrosis (PF), and MERTK inhibition has been shown to ameliorate PF. However, the mechanisms remain unclear. Here, we have investigated how MERTK inhibition attenuates bleomycin (BLM)-induced PF in mice and to elucidate the underlying mechanism(s). EXPERIMENTAL APPROACH: We analysed transcriptomic datasets from patients with idiopathic pulmonary fibrosis (IPF) to characterise expression patterns of MERTK and their correlation with clinical parameters. In a BLM-induced murine PF model, a selective MERTK inhibitor UNC5293 was evaluated in both preventive and therapeutic dosing regimens. Given its clinical translation potential, the MERTK/FLT3 inhibitor MRX2843 was evaluated in therapeutic regimen. Fibrosis severity and associated pathological changes were assessed using micro-CT, pulmonary function tests and histopathological analysis. Underlying mechanisms were further investigated in human and mouse-derived macrophages, using flow cytometry and immunofluorescence. KEY RESULTS: MERTK expression was up-regulated in pulmonary macrophages of patients with IPF and was negatively correlated with lung function parameters. In the BLM-induced PF model, UNC5293 attenuated fibrosis and improved pulmonary compliance and capacity, even when administration was initiated during the fibrotic phase. MRX2843 alleviated histological fibrosis but did not improve pulmonary function. Mechanistically, MERTK inhibition concurrently suppressed macrophage M2 polarisation-involving the PI3K/Akt signalling pathway and efferocytosis-and secretion of a profibrotic mediator osteopontin (SPP-1), thereby synergistically inhibiting the fibrotic process. CONCLUSIONS AND IMPLICATIONS: MERTK inhibition represents a promising therapeutic strategy that ameliorates fibrosis by orchestrating suppression of M2 polarisation and SPP-1 pathogenic pathways, thereby restoring pulmonary function.