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Li, C. ; Liu, Q. ; Han, L. ; Zhang, H. ; Immler, R.* ; Rathkolb, B. ; Secklehner, J.* ; Hrabě de Angelis, M. ; Yildirim, A.Ö. ; Zeuschner, D.* ; Nicke, A.* ; Carlin, L.M.* ; Sperandio, M.* ; Stöger, T. ; Rehberg, M.

The eATP/P2×7R axis drives quantum dot-nanoparticle induced neutrophil recruitment in the pulmonary microcirculation.

Adv. Sci.:e2404661 (2024)

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Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung-specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream-suspended particles. Therefore, exact knowledge about effects of engineered NPs within the pulmonary microcirculation are instrumental for future application of this technology in patients. To unravel the real-time dynamics of intravenously delivered NPs and their effects in the pulmonary microvasculature, we employed intravital microscopy of the mouse lung. Only PEG-amine-QDs, but not carboxyl-QDs triggered rapid neutrophil recruitment in microvessels and their subsequent recruitment to the alveolar space and was linked to cellular degranulation, TNF-α, and DAMP release into the circulation, particularly eATP. Stimulation of the ATP-gated receptor P2X7R induced expression of E-selectin on microvascular endothelium thereby mediating the neutrophilic immune response. Leukocyte integrins LFA-1 and MAC-1 facilitated adhesion and decelerated neutrophil crawling on the vascular surface. In summary, this study unravels the complex cascade of neutrophil recruitment during NP-induced sterile inflammation. Thereby we demonstrate novel adverse effects for NPs in the pulmonary microcirculation and provide critical insights for optimizing NP-based drug delivery and therapeutic intervention strategies, to ensure their efficacy and safety in clinical applications.

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