| Autor: |
Cornelia Tilp, M.J. Thomas, Katrin Fundel-Clemens, K C El Kasmi, Carmen Lerner, Carolin K. Koss, Peter J. Murray, Daniela Schlösser, Fidel Ramirez, Heinrich J. Huber, Coralie Viollet, Silvia Frey, Wioletta Skronska-Wasek, Florian Gantner, Stefanie Dichtl, Christian T. Wohnhaas |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
12.01 - Idiopathic interstitial pneumonias. |
| DOI: |
10.1183/23120541.lsc-2021.92 |
| Popis: |
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial lung disease with poor prognosis. The current standard-of-care for IPF is the kinase inhibitor nintedanib, which has a distinct inhibitory profile targeting a range of tyrosine kinases. The mechanism of action of nintedanib has been well characterized for myofibroblast activity, yet remains less clear for the immune populations distributed throughout the lung. Given the proposed role of heterogeneous pulmonary macrophage populations in mediating both protective and pathogenic roles in lung fibrosis, we sought to identify repair-associated macrophage populations in mice influenced by nintedanib after 7 and 14 days post-bleomycin challenge using single cell RNA sequencing. Bleomycin exposure triggered expansion of inflammatory MHCIIhigh macrophage populations, which was partially reversed after nintedanib treatment. Concurrently, nintedanib promoted the expansion of MHCIIlow macrophages, which were linked to attenuation of lung fibrosis. Concomitantly, nintedanib promoted an increased expression of canonical macrophage repair markers in MHCIIlow macrophages. Finally, exposure of inflammatory macrophages to nintedanib in vitro resulted in attenuated expression of MHCII transcripts. In conclusion, a component of nintedanib’s protective mode of action in lung fibrosis relies on expanding distinct MHCIIlow macrophage populations and redirecting them toward a reparative phenotype. This study provides a rationale for further refinement of therapeutic kinase inhibition in fibrotic diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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