Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

• Published in: Blood 2013-01, Vol.121 (3), p.519-529
• Main Authors: Liu, Guangwei, Hu, Xuelian, Sun, Bo, Yang, Tao, Shi, Jianfeng, Zhang, Lianfeng, Zhao, Yong
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - immunology; Female; Homeostasis - immunology; Leukocyte Disorders - congenital; Leukocyte Disorders - genetics; Leukocyte Disorders - immunology; Leukopoiesis - immunology; Male; MAP Kinase Signaling System - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - enzymology; Myeloid Progenitor Cells - immunology; Neutrophils - cytology; Neutrophils - enzymology; Neutrophils - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - immunology; Protein Phosphatase 2C; Respiratory Burst - immunology; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-05-432674

Neutrophils are critically involved in host defense and tissue damage. Intrinsic molecular mechanisms controlling neutrophil differentiation and activities are poorly defined. Herein we found that p53-induced phosphatase 1(Wip1) is preferentially expressed in neutrophils among immune cells. The Wip1 expression is gradually up-regulated during the differentiation of myeloid precursors into mature neutrophils. Wip1-deficient mice and chimera mice with Wip1−/− hematopoietic cells had an expanded pool of neutrophils with hypermature phenotypes in the periphery. The in vivo and in vitro studies showed that Wip1 deficiency mainly impaired the developing process of myeloid progenitors to neutrophils in an intrinsic manner. Mechanism studies showed that the enhanced development and maturation of neutrophils caused by Wip1 deficiency were mediated by p38 MAPK-STAT1 but not p53-dependent pathways. Thus, our findings identify a previously unrecognized p53-independent function of Wip1 as a cell type-specific negative regulator of neutrophil generation and homeostasis through limiting the p38 MAPK-STAT1 pathway. •Phosphatase Wip1 negatively regulates neutrophil development.•Wip1 regulates neutrophil development via p38 MAPK-STAT1.