Abstract Secreted phosphoprotein 1-positive (SPP1+) macrophages play a critical role in the progression of silicosis, but their regulatory mechanisms remain unclear. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics to characterize crucial macrophage subpopulations and their associated regulatory pathways during silicosis. Our results demonstrate that silica exposure significantly promotes the accumulation of SPP1 + macrophages within silicotic nodules. These macrophages contribute to inflammation by releasing pro-inflammatory cytokines such as TNF-α, MCP-1, and IL-6. Concurrently, they exhibit elevated ACTA2 RNA transcription levels, which enhances TGF-β production and drives fibrotic progression. These functional transitions are regulated by the ERK1/2 and JNK signaling pathways. Inhibition of SPP1 markedly attenuated silica-induced lung inflammation and fibrosis. Moreover, plasma SPP1 levels in silicosis patients were strongly correlated with disease onset and severity. Collectively, our findings indicate that SPP1 + macrophages are involved throughout the entire course of silicosis development, under the regulation of ERK/JNK signaling. Targeting SPP1 + macrophages may thus represent a promising therapeutic strategy for silicosis.
Sun et al. (Thu,) studied this question.