Immunomodulatory Effects of Nintedanib on Human Blood Monocytes/Macrophages from Patients with Idiopathic Pulmonary Fibrosis

Background: Nintedanib (NTD) is an inhibitor of several tyrosine kinases whose role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is well recognized. Therefore, NTD was approved for the management of IPF about ten years ago. NTD has been demonstrated to have immunomodulatory effects in vitro. We now evaluated the effects of NTD on monocyte/macrophage phenotype isolated from IPF patients treated with NTD. Methods: Monocytes were isolated from IPF patients naïve for treatments and used as such or differentiated into M1- and M2-like macrophages. The cellular phenotype (characterized by the expression pro- and anti-fibrotic surface markers) and responsiveness (characterized by oxidative stress and cytokine expression/release) were evaluated, at T0 (before treatment starts) and after 6 months of treatment with a 150 mg capsule of NTD twice a day (T1). Results: Following differentiation, both M1 and M2 macrophage populations, derived from monocytes isolated from patients treated with NTD, present a higher percentage of cells positive for anti-fibrotic CD80/CD86 and expressing less profibrotic CD206/CD163. Importantly, gene expression and release of the pro-fibrotic factor TGF-β were significantly decreased at T1. Conclusions: These results show that although it does not have a direct effect on monocyte phenotype/responsiveness, NTD in vivo appears to prime monocytes to differentiate preferentially towards an anti-fibrotic macrophage phenotype, suggesting that it has an immunomodulatory effect on macrophage polarization. This data leads us to hypothesize that NTD could also induce this change in vivo, thus contributing to the improvement of the patient's fibrotic state.