Abstract Our lungs have been exposed to inhaled materials since hundred million years, but the quality of inhaled particles has changed rather recently. Because of shape and biopersistence, some nanomaterials (NM), in particular carbon-based types, are of concern to pose respiratory risks related to tissue injury and fibrosis. Local pulmonary inflammation, a well-known and generic commonality for inhaled NMs, is a key event considered to precede pathological outcomes such as fibrosis. To better understand which cell types and cell circuits are involved in initiation and continuation of the inflammatory response, we have recently performed a single-cell transcriptomics study of NM exposed mouse lungs after various time points. Interestingly rigid multi-walled CNT (MWCNT) caused persistent depletion of the resident alveolar macrophage pool accompanied by accumulation of a transitional state of monocyte-derived macrophages, characterized by high levels of SPP1 expression. NicheNet analysis predicted pro-fibrotic interactions with the fibroblast niche, confirmed by in vitro studies where conditioned medium from MWCNT exposed macrophages or recombinant SPP1 triggered collagen expression in an alveolar organoid model. To understand the relevance of this SPP1+ macrophage state for the development of fibrotic lung diseases, we performed computational analysis with various clinical data sets and revealed a significant resemblance of transitional macrophages to the pro-fibrotic macrophage phenotype of idiopathic pulmonary fibrosis (IPF). Elevated SPP1 expression could be associated with disease severity and even mortality in IPF patients. In conclusion, we demonstrate that fibre-shaped NMs can trigger a pattern of dynamic macrophage perturbation similar as observed during pulmonary fibrosis pathogenesis.
Han et al. (Thu,) studied this question.