Multi-omics data reveal that SAA1 + fibroblasts exacerbate periodontitis by regulating macrophage inflammation and chemotaxis.

BACKGROUND

Traditional techniques are limited in their ability to analyze the complex interaction mechanisms among multiple cell types within the periodontal microenvironment, thereby restricting the development of targeted therapies for periodontitis (PD). Utilizing multiomics technologies to investigate the interaction networks of key cell clusters can systematically uncover regulatory mechanisms and identify critical therapeutic targets.

METHODS

Through integrative analysis of single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk transcriptome datasets from periodontal tissues, we systematically characterized the spatial architecture and intercellular communication networks within the inflammatory periodontal microenvironment, identifying a functionally serum amyloid A1 + fibroblasts (SAA1 + Fib) that critically drives disease progression. Combined bioinformatics and functional validations (in vitro and in vivo) revealed the proinflammatory role of SAA1 + Fib, demonstrating their unique transcriptional profile and mechanistic contributions to periodontal inflammation.

RESULTS

This study successfully constructed a single-cell transcriptome atlas comprising 65,979 periodontal tissue cells and identified an SAA1 + fibroblast subpopulation with key functions. Cell communication analysis revealed that this subpopulation mediates the infiltration of myeloid cells, such as macrophages, to the lesion site by secreting chemokine-related signaling molecules, including members of the SAA, CXCL, and CSF families. Animal experiments confirmed a significant increase in SAA1 expression levels in both the gingival tissue and peripheral blood of periodontitis model mice. Gene function studies indicated that SAA1 knockout resulted in reduced migration ability and enhanced proliferation activity of L929 cells, while significantly decreasing the secretion of inflammatory factors such as IL-6 and TNF-α. In a co-culture system of L929 cells and RAW264.7 cells, SAA1 knockout not only diminished the chemotactic effect of fibroblasts on macrophages but also suppressed the secretion of inflammatory factors and inhibited M1 polarization of macrophages. Mechanistic studies indicated that these effects were likely mediated by the suppression of NF-κB signaling pathway activity in RAW264.7 cells.

CONCLUSION

We elucidated the pro-inflammatory properties of SAA1 + Fib and their role in promoting macrophage infiltration, targeting SAA1 offers a new approach for the treatment of PD.