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Objectives and questions: Periprosthetic joint infection (PJI) is associated with high rates of reinfection and aseptic loosening despite successful pathogen eradication. We hypothesized that PJI induces persistent immune reprogramming that disrupts vascular integrity and bone homeostasis, establishing a post-infectious failure phenotype.

Material and methods: Peripheral blood, bone marrow, periprosthetic bone (n=64), and capsule specimens (n=69) were obtained from primary arthroplasty controls and two-stage PJI revisions (explantation, reimplantation). Analyses included flow cytometry, ELISA, µCT, histology, immunofluorescence, gene expression, and functional osteoclast assays. PBMCs and isolated monocytes were stimulated with biofilm supernatant or TNF-α to assess context-dependent checkpoint induction and differentiation.

Results: PJI was characterized by systemic and local expansion of checkpoint-expressing monocytes in blood (48.0% vs 96.8%, p<0.001) and marrow (20.1% vs 55.7%, p=0.003), accompanied by elevated circulating ligand levels. Biofilm supernatant induced PD-1 upregulation only in stimulated PBMC cultures, not in isolated monocytes; TNF-α showed similar dependence on multicellular inflammatory crosstalk, indicating network-driven immune activation rather than direct bacterial signaling. Functionally, PJI-derived monocytes demonstrated exaggerated osteoclast differentiation and resorption. In bone, reduced bone volume fraction, trabecular thickness, and mineral density coexisted with osteoclast predominance and suppressed osteogenic signaling. In the capsule, increased vessel density with reduced mural cell coverage and enhanced fibrosis reflected immature angiogenesis. These structural and molecular alterations persisted at reimplantation.

Discussion and conclusions: PJI induces durable immune reprogramming across compartments, driving checkpoint imbalance, osteoclast activation, impaired osteogenesis, and aberrant vascular remodeling. Prosthesis failure after PJI should be understood as a manifestation of sustained immune dysregulation rather than isolated infection. Targeting post-infectious immune network remodeling may be required to restore osteo-vascular homeostasis and improve long-term outcomes.