PD ‐ L1 + Senescent Macrophages Reshape the Immune Microenvironment of Periodontitis via PI3K / AKT Pathway Activation

ABSTRACT Objective To investigate the senescence/apoptosis phenotype of PD‐L1 + macrophages in gingival tissues with periodontitis and their relationship with the PI3K/AKT pathway. Methods Immunohistochemistry and multiplex immunofluorescence were used to assess PD‐L1 expression and its colocalization with CD68/CD163 and p21 in human periodontitis gingival tissues. Public single‐cell and bulk transcriptomic datasets were integrated to characterize PD‐L1 + macrophages. RAW264.7 senescence models were induced separately with Porphyromonas gingivalis LPS or H 2 O 2 , followed by lentiviral shRNA knockdown of PD‐L1 to evaluate SASP, apoptosis‐related markers, and PI3K/AKT signaling. Results PD‐L1 was markedly upregulated in periodontitis gingiva and enriched in p21 + macrophages. Single‐cell and bulk analyses showed expansion of PD‐L1 + macrophages accompanied by upregulation of CDKN1A/CDKN2A and SASP factors such as IL‐6 and IL‐1β, increased expression of BCL2 family members, and activation of PI3K/AKT signaling. In the in vitro senescence model, PD‐L1, p‐PI3K, and p‐AKT were elevated, and cells exhibited resistance to apoptosis. PD‐L1 knockdown reduced PI3K/AKT activity, alleviated senescence and SASP, and promoted apoptosis. Conclusion In periodontitis, PD‐L1 + senescent macrophages maintain inflammatory amplification and resistance to apoptosis through activation of the PI3K/AKT pathway. The PD‐L1/PI3K/AKT axis may represent a potential immunomodulatory target for periodontitis treatment.