Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner

Abstract

Key Points• Wip1 controls antigenindependent B-cell development in the bone marrow via a p53-dependent pathway.• Wip1 is essential to prevent an aging-related decline in B-cell development.Wild-type p53-induced phosphatase 1 (Wip1), a phosphatase previously considered as an oncogene, has been implicated in the regulation of thymus homeostasis and neutrophil maturation. However, the role of Wip1 in B-cell development is unknown. We show that Wip1-deficient mice exhibit a significant reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen. A reciprocal transplantation approach revealed a cell-intrinsic defect in early B-cell precursors caused by Wip1 deficiency. Further experiments revealed that Wip1 deficiency led to a sustained activation of p53 in B cells, which led to increased level of apoptosis in the pre-B-cell compartment. Notably, the impairment of B-cell development in Wip1-deficient mice was completely rescued by genetic ablation of p53, but not p21. Therefore, loss of Wip1 phosphatase induces a p53-dependent, but p21-independent, mechanism that impairs B-cell development by enhancing apoptosis in early B-cell precursors. Moreover, Wip1 deficiency exacerbated a decline in B-cell development caused by aging as evidenced in mice with aging and mouse models with serial competitive bone marrow transplantation, respectively. Our present data indicate that Wip1 plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development. (Blood. 2015;126(5):620-628)

Phosphatase Wip1 in Immunity: An Overview and Update

“…Wip1-deficient mice exhibit a remarkable reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen (33). Through the establishment of mixed chimerism, studies showed that the decreased number of B cells found in Wip1-deficient mice was mainly caused by the impaired development of B cells during the pre-B-cell stage as Wip1-deficient bone marrow cells (BMCs) differentiated into B cells in a lower efficiency compared with the WT BMCs and Wip1 deficiency also led to more cell death in pre-B cells (33). Since DNA recombination events induce DNA damage response which leads to p53 activation and apoptosis during B-cell development (34, 35), the activation of p53 results in the upregulation of Wip1 which could dampen p53 protein level (33).…”

“…Therefore, Wip1 serves as a negative feedback regulator to maintain the homeostatic level of p53 to support B-cell development, especially at the pre-B-cell stage. Moreover, Wip1 is also suggested to play a critical role in preventing an aging-related decline in B-cell development as Wip1 deficiency exacerbates the impairment of the pre-B-cell development both in physiological aging and experimentally forced replicative aging (33). …”

Phosphatase Wip1 Masters IL-17–producing Neutrophil-mediated Colitis in Mice

“…12,13 We recently demonstrated that Wip1 critically regulates bone marrow granulocyte and B-cell development and maturation. 14,15 With LPS-induced acute lung damage and ischemia/reperfusion injury mouse models, we demonstrated that Wip1-deficient mice displayed enhanced inflammatory activity such as higher TNF-a, IL-12, IL-6, and IL-1b production as well as enhanced migration ability in a cell-intrinsic manner, 3,16 indicating that phosphatase Wip1 negatively regulates neutrophil proinflammatory cytokine production and migration. In this study, Wip1 deficiency significantly increased IL-17 production by neutrophils.…”

Wipping p53 into subservience in B-cell development

“…3 The current report reveals that in the absence of Wip1, the formation of the pre-B-cell compartment is impaired. 1 The early pre-B-cell stage represents one of the major windows for cell proliferation in early B-cell development, as coordinated interleukin-7 and pre-B-cell receptor signaling drives the proliferation of cells carrying a functional immunoglobulin (Ig) heavy-chain gene, 4 and it is therefore reasonable that targeting of this developmental stage impairs the formation of mature B-lineage cells. p53 can block cell-cycle progression by induction of p21 expression; however, deletion of p21 could not rescue B-cell development in Wip1-deficient mice, arguing against the idea that the loss of pre-B cells would be due to a disruption of cell-cycle progression.…”

“…1 Mice deficient in the Wip1 gene display increased apoptosis in the pre-B-cell compartment and a reduction in peripheral B-cell numbers, a phenotype exacerbated with age and upon serial transplantations of bone marrow (BM) cells. 1 Even though Wip1 has the ability to modulate multiple signaling pathways in the cell, the restoration of B-cell numbers upon deletion of the p53 gene 1 suggests that an autoregulatory loop between p53 and Wip1 is of importance to maintain normal production of B lymphocytes.…”