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

Abstract

SUMMARYTartrate-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 identi®ed; however, knockout mice lacking TRAP have a skeletal phenotype caused by an intrinsic osteoclast defect. To investigate a putative function for TRAP in macrophages (Mw), we investigated proin¯ammatory responses and systemic microbial clearance in knockout mice compared with age-and gendermatched congenic wild-type mice. Phorbol 12-myristate 13-acetate (PMA)-stimulated and interferon-c (IFN-c)-induced superoxide formation was enhanced in peritoneal Mw lacking TRAP; nitrite production in response to stimulation with lipopolysaccharide (LPS) and IFN-c was also increased. In addition, secretion of the proin¯ammatory cytokines, tumour necrosis factor-a (TNF-a), interleukin (IL)-1b and IL-12, was signi®cantly greater in TRAP-de®cient Mw when stimulated with LPS, with or without addition of either TNF-a or IFN-c. The activity of tartratesensitive (lysosomal) acid phosphatase was increased in Mw from the knockout mice but activities of the lysosomal hydrolases N-acetyl b-glucosaminidase and acid b-glucuronidase were unchanged, indicating selective activation of compensatory acid phosphatase activity. Evidence of impaired Mw 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 Mw. As peritoneal Mw and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro, TRAP may directly or indirectly in¯uence recruitment of Mw to sites of microbial invasion. Our study shows that TRAP participates in the in¯ammatory response of the Mw and in¯uences effector signalling pathways in innate immunity.

Complex Regulation of Tartrate-resistant Acid Phosphatase (TRAP) Expression by Interleukin 4 (IL-4)

“…still not clear. TRAP is highly expressed by osteoclasts and is important for bone matrix degradation (2)(3)(4)(5)(6). TRAP is also expressed in macrophages (50), dendritic cells, and many other tissues (51).…”

“…TRAP plays an important role in bone resorption. Mice lacking TRAP exhibited a defect in endochondral ossification, mild osteopetrosis, and disordered macrophage inflammatory responses (2)(3)(4). Conversely, transgenic mice overexpressing TRAP resulted in a decrease in trabecular bone density with characteristic mild osteoporosis (5).…”

Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells

“…Further, several proteins participating in ROS signaling and secretion of pro-inflammatory cytokines were upregulated in the multipotent state (e.g. tartrate-resistant acid ATPase ϩ5.3-fold and adenosine deaminase ϩ2.1-fold; (58,59)). Notably, also components of the adaptive immune response showed up-regulation in LS ϩ K cells, including the "don't-eat-me" signal CD47 (ϩ1.8-fold; (60)) and the B-cell immunity receptor Igh-6 (ϩ9.9-fold).…”

Molecular characterization and expression analysis of purple acid phosphatase gene from pearl oyster Pinctada martensii

“…In mammals, PAPs are involved in the immune response (Brehme et al, 1999;Bune et al, 2001;Hayman et al, 2001;Räisänen et al, 2005). This report is supported by the finding that PAPs co-localize with alpha2-macroglobulin (a 2 M), and its expression can be upregulated after lipopolysaccharide (LPS) stimulation (Brehme et al, 1999;Hayman et al, 2001).…”

“…Overexpression of PAPs in a macrophage-like cell line resulted in increased reactive oxygen species (ROS) production and an enhanced capacity for bacterial killing (Halleen et al, 2003;Räisänen et al, 2005). Furthermore, PAP knockout mice showed a reduced capacity to clear bacterial pathogens from the peritoneal cavity in vivo (Bune et al, 2001). In osteoclasts, PAPs may participate in bone resorption and are used as histochemical markers (Hayman et al, 1996;Feder et al, 2012).…”