Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus

Abstract

Tartrate-resistant acid phosphatase (TRAP) is a lysosomal di-iron protein of mononuclear phagocytes and osteoclasts. Hitherto, no role for the enzyme in immunity has been identified; however, knockout mice lacking TRAP have a skeletal phenotype caused by an intrinsic osteoclast defect. To investigate a putative function for TRAP in macrophages (Mφ), we investigated proinflammatory responses and systemic microbial clearance in knockout mice compared with age- and gender-matched congenic wild-type mice. Phorbol 12-myristate 13-acetate (PMA)-stimulated and interferon-γ (IFN-γ)-induced superoxide formation was enhanced in peritoneal Mφ lacking TRAP; nitrite production in response to stimulation with lipopolysaccharide (LPS) and IFN-γ was also increased. In addition, secretion of the proinflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-12, was significantly greater in TRAP-deficient Mφ when stimulated with LPS, with or without addition of either TNF-α or IFN-γ. The activity of tartrate-sensitive (lysosomal) acid phosphatase was increased in Mφ from the knockout mice but activities of the lysosomal hydrolases N-acetyl β-glucosaminidase and acid β-glucuronidase were unchanged, indicating selective activation of compensatory acid phosphatase activity. Evidence of impaired Mφ function in vivo was obtained in TRAP knockout mice, which showed delayed clearance of the microbial pathogen, Staphylococcus aureus, after sublethal intraperitoneal inoculation. After microbial challenge, peritoneal exudates obtained from TRAP knockout mice had a reduced population of Mφ. As peritoneal Mφ and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro, TRAP may directly or indirectly influence recruitment of Mφ to sites of microbial invasion. Our study shows that TRAP participates in the inflammatory response of the Mφ and influences effector signalling pathways in innate immunity.