Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia

Fiedler, Katja; Sindrilaru, Anca; Terszowski, Grzegorz; Kókai, Enikö; Feyerabend, Thorsten B.; Bullinger, Lars; Rodewald, Hans Reimer; Brunner, Cornelia

doi:10.1182/blood-2010-04-281170

Cited by 103 publications

(96 citation statements)

References 45 publications

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“…23,24 In accordance with the in vitro observation, we detected a significantly higher percentage of mature neutrophils and moderately lower percentages of immature neutrophils and promyelocytes/ myelocytes in BMCs of Wip1-deficient mice than controls ( Figure 4A-B). Moreover, Wip1-deficient neutrophils in full or mixed chimeras also revealed a higher proportion of mature phenotype and lower percentages of immature neutrophils than WT controls as determined by the expression of CD11b/Gr1 (Figure 4C-D).…”

Section: Loss Of Wip1 Expression Promotes Differentiation Of Myeloid supporting

confidence: 88%

“…To dissect the potential intrinsic role of Wip1 in hematopoietic differentiation, we evaluated its expression throughout myeloid development in highly purified cell populations from BM. As granulocytic differentiation proceeds in BM through GMPs (CD34 hi CD16/32 hi ), CD11b int Gr-1 int promyelocytes/myelocytes, CD11b low Gr-1 hi immature neutrophils (imNeu), and CD11b hi Gr-1 hi mature neutrophils (mNeu), 23,24 the expression of Wip1 steadily increases, whereas hematopoietic stem cells (HSCs) and progenitor cells expressed relatively low levels of Wip1 ( Figure 1B). Similar mRNA levels of housekeeping gene HPRT in these cells were observed (supplemental Figure 1C).…”

Section: Characterization Of Wip1 Expression In Neutrophilsmentioning

confidence: 99%

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Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Liu

Sun

et al. 2013

Blood

104

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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...

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Section: Loss Of Wip1 Expression Promotes Differentiation Of Myeloid supporting

confidence: 88%

Section: Characterization Of Wip1 Expression In Neutrophilsmentioning

confidence: 99%

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Liu

Sun

et al. 2013

Blood

104

View full text Add to dashboard Cite

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“…On the basis of flow cytometric analysis of CD11b and Gr-1 expression, bone marrow neutrophils can be divided into three populations: promyelocytes/myelocytes, immature neutrophils, and mature neutrophils (18). Compared to WT bone marrow, we found a significant increase in the percentage and number of neutrophils in the KI bone marrow, with marked skewing toward a mature phenotype (Fig.…”

Section: Resultsmentioning

confidence: 84%

The Loss of RGS Protein-Gα_i2 Interactions Results in Markedly Impaired Mouse Neutrophil Trafficking to Inflammatory Sites

Cho

Kamenyeva

Yung

et al. 2012

Molecular and Cellular Biology

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c Neutrophils are first responders rapidly mobilized to inflammatory sites by a tightly regulated, nonredundant hierarchy of chemoattractants. These chemoattractants engage neutrophil cell surface receptors triggering heterotrimeric G-protein G␣ i subunits to exchange GDP for GTP. By limiting the duration that G␣ i subunits remain GTP bound, RGS proteins modulate chemoattractant receptor signaling. Here, we show that neutrophils with a genomic knock in of a mutation that disables regulator of G-protein signaling (RGS)-G␣ i2 interactions accumulate in the bone marrow and mobilize poorly to inflammatory sites. These defects are attributable to enhanced sensitivity to background signals, prolonged chemoattractant receptor signaling, and inappropriate CXCR2 downregulation. Intravital imaging revealed a failure of the mutant neutrophils to accumulate at and stabilize sites of sterile inflammation. Furthermore, these mice could not control a nonlethal Staphylococcus aureus infection. Neutrophil RGS proteins establish a threshold for G␣ i activation, helping to coordinate desensitization mechanisms. Their loss renders neutrophils functionally incompetent.

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“…with 1.5 ml of thioglycollate broth (TG; Sigma-70157) or PBS as a control. After 6 h, peritoneal exudate cells were harvested by peritoneal lavage with 20 ml cold PBS as described previously (23).…”

Section: Induction Of Sterile Peritonitismentioning

confidence: 99%

Phosphatase Wip1 Negatively Regulates Neutrophil Migration and Inflammation

Sun

Liu

et al. 2014

The Journal of Immunology

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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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Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia

Cited by 103 publications

References 45 publications

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

The Loss of RGS Protein-Gα_i2 Interactions Results in Markedly Impaired Mouse Neutrophil Trafficking to Inflammatory Sites

Phosphatase Wip1 Negatively Regulates Neutrophil Migration and Inflammation

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Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia

Cited by 103 publications

References 45 publications

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

The Loss of RGS Protein-Gαi2 Interactions Results in Markedly Impaired Mouse Neutrophil Trafficking to Inflammatory Sites

Phosphatase Wip1 Negatively Regulates Neutrophil Migration and Inflammation

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The Loss of RGS Protein-Gα_i2 Interactions Results in Markedly Impaired Mouse Neutrophil Trafficking to Inflammatory Sites