Alteration of human macrophage phenotypes by the anti-fibrotic drug nintedanib

Nessrine Bellamri (1) , Claudie Morzadec (1) , Audrey Joannes (1) , Valérie Lecureur (1) , Lutz Wollin (2) , Stéphane Jouneau (1, 3) , Laurent Vernhet (1)

1 Irset - Institut de recherche en santé, environnement et travail
2 Boehringer Ingelheim Pharma GmbH & Co. KG
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]

The tyrosine kinase inhibitor, Nintedanib (NTD), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In cell-free systems, NTD was recently shown to inhibit kinase activity of the human recombinant colony-stimulating factor 1 (CSF1) receptor (CSF1R) which mediates major functions of pulmonary macrophages. In the present study, we have investigated the effects of NTD on the phenotype of human monocyte-derived macrophages controlled by CSF1 in order to identify its anti-inflammatory properties via CSF1R inhibition. NTD (0.01 to 1 μM) prevented the CSF1-induced phosphorylation of CSF1R and activation of the downstream signaling pathways. NTD, like the CSF1R inhibitor GW2580, significantly decreased the adhesion of macrophages and production of the chemokine ligand (CCL) 2. NTD also altered the polarization of macrophages to classical M1 and alternative M2a macrophages. It reduced the secretion of several pro-inflammatory and/or pro-fibrotic cytokines (IL-1β, IL-8, IL-10 and CXCL13) by M1 macrophages but did not prevent the expression of M1 markers. While NTD (50-200 nM) partially blocked the synthesis of M2a markers (CD11b, CD200R, CD206, and CD209), it did not reduce synthesis of the M2a pro-fibrotic cytokines CCL22 and PDGF-BB, and increased CCL18 release when used at its highest concentration (1 μM). The effects of NTD on macrophage polarization only was partially mimicked by GW2580, suggesting that the drug inhibits other molecules in addition to CSF1R. In conclusion, NTD alters the CSF1-controlled phenotype of human macrophages mainly by blocking the activation of CSF1R that thus constitutes a new molecular target of NTD, at least in vitro.

Mots clés: Macrophages; Polarization; Nintedanib; CSF1R; Idiopathic pulmonary fibrosis; Inflammation

Domaines: Sciences du Vivant [q-bio]

Nessrine Bellamri, Claudie Morzadec, Audrey Joannes, Valérie Lecureur, Lutz Wollin, et al.. Alteration of human macrophage phenotypes by the anti-fibrotic drug nintedanib. International Immunopharmacology, 2019, 72, pp.112-123. ⟨10.1016/j.intimp.2019.03.061⟩. ⟨hal-02119173⟩