Antimicrobial and Immune-Modulating Effects of Recombinant Pancreatitis Associated Protein in the Treatment of MRSA-Induced Severe Septic Arthritis

Septic arthritis is a severe infection caused by bacteria directly invading the synovial joints. It leads to inflammatory damage to articular cartilage and may result in significant functional impairment, with a high recurrence rate. The rapid spread of antibiotic-resistant bacterial strains has further exacerbated the threat to human health, particularly in septic arthritis cases. Based on the antibacterial activity and regenerative properties of pancreatitis associated protein (PAP), this study aims to investigate the therapeutic potential of exogenous recombinant PAP for treating methicillin-resistant Staphylococcus aureus (MRSA)-induced septic arthritis. The prepared PAP exhibited favorable bactericidal effects against both Staphylococcus aureus (S. aureus) and MRSA, with a dose-dependent manner. The antibacterial efficacy in the high-dose group was comparable to that of vancomycin. Additionally, 10 nM PAP significantly promoted the proliferation of RAW264.7 macrophages and enhanced their resistance to oxidative stress. Intra-articular injection of PAP accelerated the recovery from MRSA-induced septic arthritis by alleviating joint swelling, clearing the bacteria within the joint cavity, and mitigating inflammation. Transcriptomic results indicated that PAP administration significantly downregulated the expression of inflammatory markers and slightly increased the proportion of monocytes/macrophages. Further studies on the immunomodulatory effects of PAP revealed that it attenuated lipopolysaccharide (LPS)-induced M1 polarization and markedly diminished the expression of pro-inflammatory cytokines, including TNF-α, IFN-γ, and IL-6. Meanwhile, PAP partially induced M2 polarization of macrophages and elevated anti-inflammatory IL-4 levels. In conclusion, PAP exhibited antibacterial, tissue repair, and immunomodulatory activities, highlighting its potential as a therapeutic candidate for septic arthritis.