Abstract
Circulating immune cell populations have been shown to contribute to interstitial lung disease (ILD). In this study, we analysed circulating and lung resident monocyte populations, and assessed their phenotype and recruitment from the blood to the lung in ILD. Flow cytometry analysis of blood samples for quantifying circulating monocytes was performed in 105 subjects: 83 with ILD (n=36, n=28 and n=19 for nonspecific interstitial pneumonia, hypersensitivity pneumonitis and connective-tissue disease-associated ILD, respectively), as well as 22 controls. Monocyte localisation and abundance were assessed using immunofluorescence and flow cytometry of lung tissue. Monocyte populations were cultured either alone or with endothelial cells to assess fractalkine-dependent transmigration pattern. We show that circulating classical monocytes (CM) were increased in ILD compared with controls, while nonclassical monocytes (NCM) were decreased. CM abundance correlated inversely with lung function, while NCM abundance correlated positively. Both CCL2 and CX3CL1 concentrations were increased in plasma and lungs of ILD patients. Fractalkine co-localised with ciliated bronchial epithelial cells, thereby creating a chemoattractant gradient towards the lung. Fractalkine enhanced endothelial transmigration of NCM in ILD samples only. Immunofluorescence, as well as flow cytometry, showed an increased presence of NCM in fibrotic niches in ILD lungs. Moreover, NCM in the ILD lungs expressed increased CX3CR1, M2-like and phagocytic markers. Taken together, our data support that in ILD, fractalkine drives the migration of CX3CR1+ NCM to the lungs, thereby perpetuating the local fibrotic process.
Abstract
The compartmental imbalance of fractalkine mediates the migration of nonclassical monocytes into fibrotic lung tissues. Furthermore, nonclassical monocyte-derived cells show a M2-like and phagocytic phenotype in ILD lungs. http://bit.ly/2CMFWex
Footnotes
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Author contributions: Conception and design: F.R. Greiffo, O. Eickelberg and I.E. Fernandez. Experimental work, analysis and interpretation: F.R. Greiffo, M. Frankenberger, D. Dietel, V. Viteri-Alvarez, J. Behr, O. Soehnlein, O. Eickelberg and I.E. Fernandez. Intellectual content: F.R. Greiffo, M. Frankenberger, D. Dietel, A. Ortega-Gomez, J.S. Lee, A. Hilgendorff, J. Behr, O. Soehnlein, O. Eickelberg and I.E. Fernandez. Drafting the manuscript: F.R. Greiffo, O. Eickelberg and I.E. Fernandez. Editing the manuscript: F.R. Greiffo, O. Eickelberg and I.E. Fernandez.
Conflict of interest: V. Viteri-Alvarez has nothing to disclose.
Conflict of interest: M. Frankenberger has nothing to disclose.
Conflict of interest: D. Dietel has nothing to disclose.
Conflict of interest: A. Ortega-Gomez has nothing to disclose.
Conflict of interest: J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech, Celgene and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: A. Hilgendorff has nothing to disclose.
Conflict of interest: J. Behr has nothing to disclose.
Conflict of interest: O. Soehnlein has nothing to disclose.
Conflict of interest: O. Eickelberg reports grants from Ministry of Research and Education Germany, during the conduct of the study; personal fees for advisory board work from Blade Therapeutics, Pieris and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: I.E. Fernandez has nothing to disclose.
Conflict of interest: F.R. Greiffo has nothing to disclose.
Support statement: This work was supported by the Helmholtz Association, German Center for Lung Research (DZL), the CPC Research School, and an ERS short-term fellowship (to F.R. Greiffo). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 6, 2018.
- Accepted October 31, 2019.
- Copyright ©ERS 2020
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