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Le macrophage dans la fibrose pulmonaire idiopathique : effets du nintédanib et expression du biomarqueur pronostique CXCL13

Abstract : Nintedanib (NTD) is an antifibrotic drug that decreases the decline of the respiratory function of patients suffering from idiopathic pulmonary fibrosis (IPF). NTD exerts antifibrotic effects by inhibiting cellular activity of various tyrosine kinase proteins. It also prevents the activity of the human recombinant CSF-1R protein that is expressed by myeloid cells, especially macrophages. Resident cells or différentiated from circulating monocytes, the macrophages contribute to IPF by secreting several proinflammatory and profibrotic cytokines. In this context, the first objective of my thesis was to determine, if by inhibiting CSF-1R activity, NTD could alter the functions of human macrophages differentiated from blood monocytes (MoDM) by CSF-1 (also called M-CSF). Our results demonstrate that NTD blocks the phosphorylation and the activity of CSF-1R in CSF-1-activated MoDM at very low concentrations that are similar to those inhibiting the human recombinant protein. By preventing CSF-1R activity, NTD reduces cell adhesion and expression of the profibrotic chemokine CCL2. Moreover, by blocking the activity of CSF1R and that of other molecular targets, NTD modulates the polarization of CSF-1-activated MoDM. It reduces the production of various interleukins and chemokines by M1 MoDM and prevents the membrane expression of M2 markers. Our results notably demonstrate that NTD significantly inhibits the expression of CXCL13, a prognostic biomarker of IPF. This chemokine is expressed in pulmonary tissues but its cellular origin is unclear. The second objective of my thesis was thus to characterize CXCL13 expression in pulmonary macrophages. Our results demonstrate that CXCL13 is expressed by alveolar macrophages in patients with IPF. In vitro, CXCL13 expression in activated alveolar macrophages and MoDM is controlled by TNF-α and IL-10 through the activation of the NF-κB and JAK/STAT pathways, respectively. Moreover, we demonstrate that seric concentrations of TNF-α, IL-10 and CXCL13 are correlated in patients with IPF. These results thus suggest that TNF-α and IL-10 could mediate CXCL13 expression in those patients.
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Submitted on : Tuesday, July 7, 2020 - 10:29:47 AM
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Nessrine Bellamri. Le macrophage dans la fibrose pulmonaire idiopathique : effets du nintédanib et expression du biomarqueur pronostique CXCL13. Médecine humaine et pathologie. Université Rennes 1, 2019. Français. ⟨NNT : 2019REN1B067⟩. ⟨tel-02874584v2⟩

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