期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 9, 页码 4115-4131出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64772
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资金
- Cancer Society
- Childhood Cancer Society
- Swedish Society of Medical Research
- Olle Engqvist Byggmastare
- Fundacao para a Ciencia e a Tecnologia [SFRH/BD/47926/2008]
- OE and Edla Johanssons Foundation
- Lars Hierta Memorial Foundation
- Tore Nilsson Foundation
- Grochinsky Foundation
- Swedish Medical Society
- Swedish Research Council
- European Commission 7th framework Program Marie Curie [249177]
- Ake Olsson Foundation
- Jeansson Foundation
- Groschinsky Foundation
- Ake Wiberg Foundation
- Bergvall Foundation
- King Gustaf V's 80-year Foundation
- Karolinska Institutet
- Fundação para a Ciência e a Tecnologia [SFRH/BD/47926/2008] Funding Source: FCT
Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal numbers in XLN patient saliva. Murine XLN neutrophils were hyperactivated, with increased actin dynamics and migration into tissues. We provide molecular evidence that the hyperactivity of XLN neutrophils is caused by WASp in a constitutively open conformation due to contingent phosphorylation of the critical tyrosine-293 and plasma membrane localization. This renders WASp activity less dependent on regulation by PI3K. Our data show that the amplitude of WASp activity inside a cell could be enhanced by cell-surface receptor signaling even in the context in which WASp is already in an active conformation. Moreover, these data categorize XLN as an atypical congenital neutropenia in which constitutive activation of WASp in tissue neutrophils compensates for reduced myelopoiesis.
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