IntroductionPolymorphonuclear neutrophil granulocytes (PMNs or neutrophils) develop in the bone marrow (BM). They are fully equipped with a variety of granules, which contain proteases that enable the neutrophils to deliver lethal hits against invading microorganisms. 1,2 Although neutrophils are essential to host defense against intruding microorganisms and play a critical role in initiating inflammation and innate immunity, they also contribute to the pathology of various acute and chronic inflammatory conditions. 3,4 In this manner, means to properly control the development, homeostasis, and functional activities of neutrophils is of central importance to mounting robust host defense responses and simultaneously avoiding tissue damage. 5,6 However, the molecular mechanisms that accomplish this balanced effect remain poorly understood.Wild-type (WT) p53-induced phosphatase 1 (Wip1, also called PP2C␦), which is encoded by protein phophatase magnesiumdependent 1delta (PPm1D), is a serine/threonine protein phosphatase belonging to the type 2C␦ protein phosphatases. 7 It is activated by various stresses and involved in various cellular processes, such as tumorigenesis and aging. 8,9 Wip1, overexpressed in many cancers, is recognized as a novel oncogene inhibiting several p53-dependent tumor suppressor pathways, such as ATM-CHK2-p53 and p38 MAPK-p53 pathways as well as the NF-B pathway. [10][11][12][13] Currently, Wip1 is thought to be a promising drug target for cancer therapy. In the present study, after observing that Wip1 is specifically expressed in resting neutrophils among all immune cells and is up-regulated gradually during neutrophil maturation, we used Wip1-deficient mice to investigate the role of Wip1 in neutrophil development and homeostasis. Notably, Wip1-deficient mice displayed neutrophilia with significantly expanded granulocytic differentiation and hypermaturation phenotype in a cell-intrinsic and specific manner. Thus, phosphatase Wip1, as a key feedback regulator, negatively controls granulocytopoiesis and peripheral neutrophil homeostasis. Methods MiceC57BL/6 and CD45.1 ϩ mice were purchased from Beijing University Experimental Animal Center (Beijing, China). Wip1 Ϫ/Ϫ , p53 ϩ/Ϫ , and p38 ϩ/Ϫ mice were kindly provided by the Key Laboratory of Human Diseases Comparative Medicine, the Ministry of Public Health (Beijing, China). Wip1 Ϫ/Ϫ mice have been described 10,14 and backcrossed to the C57BL/6 background in our laboratory. Wip1 Ϫ/Ϫ and p53 ϩ/Ϫ mice were mated to obtain Wip1 Ϫ/Ϫ p53 Ϫ/Ϫ double-knockout mice. All mice were bred and maintained in specific pathogen-free conditions. Sex-matched littermate mice 6-12 weeks of age were mainly used for experiments unless otherwise noted. Complete or mixed chimeras were generated by transferring 1 to 2 ϫ 10 7 BM cells (BMCs) from either WT and/or Wip1KO mice into lethally irradiated mice. 15,16 Animal protocols were approved by the Animal Ethics Committee of the Institute of Zoology, Beijing, China. *G.L., X.H., and B.S. contributed equally to this st...

The lymphocyte-monocyte ratio (LMR) is a systemic inflammatory marker for prediction of disease development, progress, and survival. Recently, a genome-wide association study identified genetic variations in ITGA4 and HLA-DRB1 that affect the LMR levels and were widely believed to be susceptibility genes for autoimmune diseases, including rheumatoid arthritis (RA). However, the role of LMR in RA patients remains unclear. The LMR level and other laboratory data of 66 RA patients, 163 osteoarthritis (OA) patients, and 131 healthy controls (HC) were compared using binary logistic regression. The correlations between LMR and disease activity and other inflammatory markers were measured using the Spearman rank test. ROC curve analyses assessed the diagnostic accuracy of LMR in RA. The LMR and lymphocyte count were significantly lower in RA patients, whereas the monocyte count was significantly higher relative to the HC group/OA patients (p < 0.01). A decreased LMR has been associated with increased disease activity (p = 0.012). In addition, the DAS28 and traditional inflammatory markers, including ESR, CRP, RDW, PLR, and NLR, and immune-related factors, such as C4, IgA, and IgM, were inversely correlated with LMR, while hemoglobin and albumin were positively correlated with LMR. The ROC curve showed that the area under the curve of LMR was 0.705 (95%CI = 0.630-0.781). The corresponding specificity and sensitivity were 82.82 and 45.45%, respectively. The present study shows that the LMR is an important inflammatory marker which could be used to identify disease activity in RA patients and to distinguish RA from OA patients.

Neutrophils are critically involved in host defense and tissue damage. Intrinsic signal mechanisms controlling neutrophil activities are poorly defined. We found that the expression of wild-type p53-induced phosphatase 1 (Wip1) in mouse and human neutrophils was downregulated quickly after neutrophil activation through JNK-microRNA-16 pathway. Importantly, the Wip1 expression level was negatively correlated with inflammatory cytokine productions of neutrophils in sepsis patients. Wip1-deficient mice displayed increased bactericidal activities to Staphylococcus aureus and were hypersensitive to LPS-induced acute lung damage with increased neutrophil infiltration and inflammation. Mechanism studies showed that the enhanced inflammatory activity of neutrophils caused by Wip1 deficiency was mediated by p38 MAPK-STAT1 and NF-κB pathways. The increased migration ability of Wip1KO neutrophils was mediated by the decreased CXCR2 internalization and desensitization, which was directly regulated by p38 MAPK activity. Thus, our findings identify a previously unrecognized function of Wip1 as an intrinsic negative regulator for neutrophil proinflammatory cytokine production and migration through multiple signal pathways.

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BackgroundRecently, stem cells derived from inflammatory dental pulp tissues (DPSCs-IPs) have demonstrated regenerative potential, but the real effect remains to be examined. This pilot study attempted to isolate DPSCs-IPs from two patients and to evaluate the feasibility and the effect of reconstructing periodontal intrabone defects in each patient.MethodsDPSCs-IPs were harvested from two patients with periodontal intrabone defects with their approval. After discussing the biological characteristics of DPSCs-IPs in each patient, DPSCs-IPs were loaded onto the scaffold material β-tricalcium phosphate and engrafted into the periodontal defect area in the root furcation. After 1, 3, and 9 months, the outcome was evaluated by clinical assessment and radiological study. Furthermore, new samples were collected and the biological characteristics of DPSCs-IPs were further studied compared with normal dental pulp stem cells. The primary cell culture success rate, cell viability, cell cycle analysis, and proliferation index were used to describe the growth state of DPSCs-IPs. In-vitro differentiation ability detection was used to further discuss the stem cell characteristics of DPSCs-IPs.ResultsAs expected, DPSCs-IPs were able to engraft and had an effect of regeneration of new bones to repair periodontal defects 9 months after surgical reconstruction. Although the success rate of primary cell culture and growth status was slightly inhibited, DPSCs-IPs expressed comparable levels of stem cell markers as well as retaining their multidifferentiation ability.ConclusionsWe developed a standard procedure that is potentially safe and technological for clinical periodontal treatment using human autologous DPSCs-IPs.Trial registrationAccording to the editorial policies, the present study is a purely observational study, so trial registration is not required.

Objective. The protease HTRA-1 is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA-1 expression are currently unknown. This study was undertaken to determine the regulatory role of Toll-like receptors (TLRs) on HTRA-1 expression in mice with collagen-induced arthritis (CIA) and in synovial cells from RA patients.Methods. HTRA-1 messenger RNA and protein production in mouse fibroblasts, mouse macrophages, and freshly isolated RA patient synovial cells treated with TLR ligands were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Arthritis incidence and severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA-1 in lipopolysaccharide (LPS)-increased arthritis incidence and severity in mice was determined using anti-HTRA-1 monoclonal antibody. The signal pathways involved in HTRA-1 expression were accessed by specific inhibitors, RNA interference, dual-luciferase reporter, and chromatin immunoprecipitation methods. Results. LPS and tenascin-C, but not the other TLR ligands tested

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