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Voss, C. ; Han, L. ; Ansari, M. ; Strunz, M. ; Haefner, V. ; Angelidis, I. ; Mayr, C.H. ; Berthing, T.* ; Zhou, Q. ; Günther, E. ; Huzain, O. ; Schmid, O. ; Vogel, U.* ; Schniering, J. ; Gaedcke, S.* ; Theis, F.J. ; Schiller, H.B. ; Stöger, T.

Toward a ToxAtlas of carbon-based nanomaterials: Single-cell RNA sequencing reveals initiating cell circuits in pulmonary inflammation.

ACS Nano 19, 39139-39156 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Understanding how nanomaterial properties drive acute lung inflammation is critical for the development of safer materials, but for low solubility carbon-based nanomaterials (CBNs) the initiation of the inflammatory response is still poorly understood. Leveraging single-cell RNA sequencing of mouse lungs, 12 h after intratracheally instillation with different CBN spherical carbon nanoparticles (CNP), tangled double-walled (DWCNT), and rigid multiwalled carbon nanotubes (MWCNT) and lipopolysaccharide (LPS) as positive control, we identified 41 cell states and delineated material-specific molecular initiation events at single-cell resolution. CBN doses were chosen to cause equal levels of moderate inflammation, assessed by airspace neutrophilia, and exposure-triggered cellular activation was tested for in vitro reproducibility. To advance future development of cell-based assays, we developed a webtool, ToxAtlas, mapping CBN-specific gene responses of interest. Despite chemical similarity, CBN elicited distinct inflammatory cytokine and cell responses via different modes of action. CNP triggered neutrophilia through alveolar epithelial activation and Cxcl1 and Csf2 expression but without apparent cell damage or macrophage activation. In contrast, CNT induced epithelial and macrophage damage, with alarmin release (IL-1α, IL-33) dominating the MWCNT response. DWCNT caused alveolar epithelial injury, and pro-inflammatory macrophage and fibroblast-derived monocyte attractant (Ccl2, Ccl7) activation. Our initiating cell circuits identify epithelial as well as early fibroblast activation, especially from alveolar type 2 cell-adjacent lipofibroblasts, as central to orchestrating the initiation of CBN-induced inflammation. These findings support the role of mesenchymal cells in early pulmonary defense, eventually priming chronic inflammation, a known cause of MWCNT exposure.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Toxatlas ; Mode Of Action (moa)/cell Circuits ; Nanomaterials ; Predictive Assays ; Pulmonary Inflammation ; Respiratory Toxicology ; Scrna-seq; Oxidative Stress; Toxicity; Nanoparticles; Nanotubes; Responses; Paradigm; Ambient
ISSN (print) / ISBN 1936-0851
e-ISSN 1936-086X
Journal ACS Nano
Quellenangaben Volume: 19, Issue: 45, Pages: 39139-39156 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
Research Unit Precision Regenerative Medicine (PRM)
Institute of Computational Biology (ICB)
Grants
European Commission
Helmholtz Association
Horizon 2020 Framework Programme
Deutsche Forschungsgemeinschaft
Deutsches Zentrum f?r Lungenforschung
201806240314]
China Scholarship Council