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

Tartrate-resistant acid phosphatase (TRAP) is a lysosomal di-iron protein of mononuclear phagocytes acid osteoclasts. Hitherto, no role Tor 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 (M phi). we investigated proinflammatory responses and systemic microbial clearance in knockout mice compared with age- and gender-matched congenic wild-type mice. Phorbol 12-myrislate 13-acetate (PMA)-stimulated and interferon-gamma (IFN-gamma)-induccd superoxide formation was enhanced in peritoneal M phi lacking TRAP: nitrite production in response to stimulation with lipopolysaccharide (LPS) and IFN-gamma was also increased. In addition, secretion of the proinflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta and IL-12, was significantly greater in TRAP-deficient M phi when stimulated with LPS, with or without addition of either TNF-alpha or IFN-gamma. The activity of tartrate-sensitive (lysosomal) acid phosphatase was increased in M phi from the knockout mice but activities of the lysosomal hydrolases N-acetyl beta -glucosaminidase and acid beta -glucuronidase were unchanged, indicating selective activation of compensatory acid phosphatase activity. Evidence of impaired M phi 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 or M phi. As peritoneal M phi and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro,, TRAP may directly or indirectly influence recruitment of M phi to sites of microbial invasion. Our study shows that TRAP participates in the inflammatory response of the M phi and influences effector signalling pathways in innate immunity.