Bune A J, Hayman A R, Evans M J, Cox T M
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Immunology. 2001 Jan;102(1):103-13. doi: 10.1046/j.1365-2567.2001.01145.x.
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 (Mphi), 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-gamma (IFN-gamma)-induced superoxide formation was enhanced in peritoneal Mphi 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)-1beta and IL-12, was significantly greater in TRAP-deficient Mphi 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 Mphi 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 Mphi 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 Mphi. As peritoneal Mphi and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro, TRAP may directly or indirectly influence recruitment of Mphi to sites of microbial invasion. Our study shows that TRAP participates in the inflammatory response of the Mphi and influences effector signalling pathways in innate immunity.
抗酒石酸酸性磷酸酶（TRAP）是一种单核吞噬细胞和破骨细胞的溶酶体双铁蛋白。迄今为止，尚未确定该酶在免疫中的作用；然而，缺乏TRAP的基因敲除小鼠具有由内在破骨细胞缺陷引起的骨骼表型。为了研究TRAP在巨噬细胞（Mphi）中的假定功能，我们研究了与年龄和性别匹配的同基因野生型小鼠相比，基因敲除小鼠中的促炎反应和全身微生物清除情况。在缺乏TRAP的腹膜巨噬细胞中，佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）刺激和干扰素-γ（IFN-γ）诱导的超氧化物形成增强；对脂多糖（LPS）和IFN-γ刺激的亚硝酸盐产生也增加。此外，在用LPS刺激时，无论是否添加TNF-α或IFN-γ，TRAP缺陷型巨噬细胞中促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β和IL-12的分泌都显著增加。基因敲除小鼠巨噬细胞中酒石酸敏感（溶酶体）酸性磷酸酶的活性增加，但溶酶体水解酶N-乙酰-β-葡萄糖苷酶和酸性β-葡萄糖醛酸酶的活性未改变，表明补偿性酸性磷酸酶活性的选择性激活。在TRAP基因敲除小鼠中获得了体内巨噬细胞功能受损的证据，这些小鼠在亚致死性腹腔接种后显示出微生物病原体金黄色葡萄球菌的清除延迟。微生物攻击后，从TRAP基因敲除小鼠获得的腹膜渗出物中巨噬细胞数量减少。由于缺乏TRAP的腹膜巨噬细胞和中性粒细胞在体外能够正常吞噬和杀死金黄色葡萄球菌，TRAP可能直接或间接影响巨噬细胞向微生物入侵部位的募集。我们的研究表明，TRAP参与巨噬细胞的炎症反应并影响先天免疫中的效应信号通路。
