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Targeting the PGRN-BMP Lysosomal Axis With NPs@PGRN Reverses Immunometabolic Dysfunction in Chronic Septic Arthritis
Congsun Li1,2,3,4,5, Jiaqi Fan6, Tao Sun1,2,3,4,5
1Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Abstract:
Chronic septic arthritis, often progressing to refractory infection due to intracellular bacterial persistence, is accompanied by dynamic macrophage immunometabolic reprogramming. Prolonged intracellular bacterial survival drives lipid metabolic remodeling in macrophages, leading to progressive accumulation of bis(monoacylglycero)phosphate (BMP), regulated by progranulin (PGRN). Mechanistically, PGRN maintains lysosomal homeostasis through direct interaction with BMP. PGRN deficiency disrupts lysosomal integrity, induces immunosuppressive polarization, and facilitates bacterial immune evasion. To address this, a dual-targeting nanoparticle system (NPs@PGRN) targeting the "PGRN-BMP-lysosome" axis was developed. NPs@PGRN restores lysosomal bactericidal capacity via PGRN replenishment, significantly reduces bacterial burdens, and reprograms macrophage immunophenotypes toward antimicrobial competence. This study elucidates the central role of lipid-immune crosstalk in chronic joint infection pathogenesis and provides a novel therapeutic strategy for it.
Insights
Chronic septic arthritis involves macrophage metabolic changes affecting bacterial persistence. A new nanoparticle therapy (NPs@PGRN) replenishes progranulin (PGRN), restoring macrophage function and clearing bacteria.
Area of Science:
- Immunology
- Cell Biology
- Drug Delivery
Background:
- Chronic septic arthritis features persistent intracellular bacteria and macrophage immunometabolic reprogramming.
- Intracellular bacterial survival alters macrophage lipid metabolism, increasing bis(monoacylglycero)phosphate (BMP) and impacting lysosomal function.
- Progranulin (PGRN) regulates lysosomal homeostasis via BMP interaction; PGRN deficiency impairs macrophage antimicrobial activity and promotes bacterial immune evasion.
Purpose of the Study:
- To investigate the role of lipid-immune crosstalk in chronic septic arthritis pathogenesis.
- To develop a novel therapeutic strategy targeting the PGRN-BMP-lysosome axis for chronic joint infections.
Main Methods:
- Development of a dual-targeting nanoparticle system (NPs@PGRN) for progranulin (PGRN) delivery.
- Assessment of NPs@PGRN efficacy in restoring lysosomal function and macrophage antimicrobial competence.
- Evaluation of bacterial burden reduction and macrophage immunophenotype reprogramming in a model of chronic septic arthritis.
Main Results:
- NPs@PGRN successfully replenished PGRN, restoring lysosomal integrity and bactericidal capacity.
- Treatment significantly reduced bacterial loads in chronic septic arthritis.
- Macrophage immunophenotypes were reprogrammed towards enhanced antimicrobial competence.
Conclusions:
- Lipid-immune crosstalk is central to chronic joint infection pathogenesis.
- Targeting the PGRN-BMP-lysosome axis with NPs@PGRN offers a promising therapeutic strategy for refractory septic arthritis.
- Restoring macrophage metabolic and lysosomal function is key to overcoming intracellular bacterial persistence.
