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 o f 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 investiga te a putative function for TRAP in macrophages (M phi). we investigated pro inflammatory responses and systemic microbial clearance in knockout mice co mpared with age- and gender-matched congenic wild-type mice. Phorbol 12-myr islate 13-acetate (PMA)-stimulated and interferon-gamma (IFN-gamma)-induccd superoxide formation was enhanced in peritoneal M phi lacking TRAP: nitrit e production in response to stimulation with lipopolysaccharide (LPS) and I FN-gamma was also increased. In addition, secretion of the proinflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 bet a and IL-12, was significantly greater in TRAP-deficient M phi when stimula ted with LPS, with or without addition of either TNF-alpha or IFN-gamma. Th e 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, Staphyloco ccus aureus, after sublethal intraperitoneal inoculation. After microbial c hallenge, peritoneal exudates obtained from TRAP knockout mice had a reduce d population or M phi. As peritoneal M phi and neutrophils lacking TRAP wer e able to phagocytose and kill S. aureus normally in vitro,, TRAP may direc tly or indirectly influence recruitment of M phi to sites of microbial inva sion. Our study shows that TRAP participates in the inflammatory response o f the M phi and influences effector signalling pathways in innate immunity.