Specific cellular perturbation patterns in lung inflammation after nanoparticle inhalation

Abstract

Inhaled nanoparticles (NP) can cause chronic inflammation; however, rapid resolution depends strongly on the type of NPs. We aim to investigate NP specific cellular perturbation during transition from acute to chronic lung inflammation. We exposed mice intratracheally to soot like carbon black (CNP), tangled double-walled (DNT) and rigid, carcinogenic multi-walled carbon nanotubes (MNT). All lungs underwent single cell RNA sequencing and BAL analysis. NPs caused comparable airspace neutrophilia at 12h, which increased until d6 for NTs and remained elevated until d28 for MNT. MNT, to a lesser extent DNT, caused persistent depletion of alveolar macrophages (AM), which were replenished by a transitional monocyte/macrophage population at d6. Interestingly, cytokine BALF levels at 12h robustly differentiated the material specific quality of initial inflammation. Furthermore, ligand-receptor pair based putative cell communication analysis uncovered NP-specific, temporal networks: CNP mediated signaling at 12h between mucous, Club cells (CC), fibroblasts (FB) and dendritic cells (DC), subsiding over a CC-monocyte (MC) interaction. DNT initiated a defined communication of AMs with DCs, expanding to MCs, interstitial macrophages (IM), endothelial cells (EC) and the alveolar epithelium (AT1) remaining at an AT1-MC-IM axis by d28. MNT initiated signaling between CCs, ciliated cells, ECs and FBs, shifting to an intense MC-FB centered interaction at d6, remaining at a faint crosstalk of MCs, ECs and FBs at d28. Our study demonstrates surprising material specific responses of varying duration and in different cellular niches. AM-toxicity offers concern and may lead to long-term damage of exposed lungs.