The pulmonary immune system orchestrates lung homeostasis and protects against environmental insults through coordinated actions of immune and structural cells. Traditional Chinese medicine recognized the functional interaction between the lungs and the large intestine more than 2000 years ago, but direct evidence for this relationship in modern biomedical research remains limited. Although inhaled nanomaterials can induce lung fibrosis, the underlying immune mechanisms and their impact on large intestine remain poorly understood. Here, we integrated spatial transcriptomics, mRNA-seq, metabolomics, microbiome profiling, and validation in vitro to investigate how multi-walled carbon nanotubes (MWCNTs) exposure affects pulmonary immune responses and gut homeostasis in mice. MWCNTs were administered to mice via oropharyngeal aspiration. We integrated spatial transcriptomics, bulk RNA sequencing, serum metabolomics, 16S rRNA microbiome profiling, and macrophage experiments in vitro. This multi-omics approach mapped pulmonary cellular alterations, identified key cell–cell signaling pathways, and examined downstream metabolic and intestinal changes provoked by MWCNTs. The results suggested that inhaled MWCNTs induced distinct spatial reorganization of pulmonary cellular architecture, characterized by macrophage- and fibroblast-enriched clusters associated with localized immune activation. Furthermore, cell–cell communication analysis identified Slamf7–Slamf7 interactions as key drivers of macrophage superactivation evidenced by excessive pro-inflammatory cytokine release. Notably, knockdown of Slamf7 in alveolar macrophages in vitro effectively attenuated the superactivation. The macrophage superactivation altered serum metabolic profiles, particularly in pathways related to energy metabolism and inflammation. Finally, lung injury extended to the distal intestine, where rectal epithelial barrier integrity was compromised, resulting in microbial and metabolic imbalance. These findings highlight the hazardous potential of inhaled MWCNTs based on macrophage superactivation induced by Slamf7 in the lung, providing mechanistic evidence for the lung–gut link described in traditional Chinese medicine. Together, our results identify molecular targets to mitigate nanomaterial immunotoxicity and inform the design and using of safer, surface-engineered MWCNTs.
Han et al. (Wed,) studied this question.