Reduced PU.1 expression underlies aberrant neutrophil maturation and function in β-thalassemia mice and patients.
β-Thalassemia is associated with several abnormalities of the innate immune system. Neutrophils in particular are defective, predisposing patients to life-threatening bacterial infections. The molecular and cellular mechanisms involved in impaired neutrophil function remain incompletely defined. We used the Hbbth3/+β-thalassemia mouse and hemoglobin E (HbE)/β-thalassemia patients to investigate dysregulated neutrophil activity. Mature neutrophils from Hbbth3/+mice displayed a significant reduction in chemotaxis, opsonophagocytosis, and production of reactive oxygen species, closely mimicking the defective immune functions observed in β-thalassemia patients. In Hbbth3/+mice, the expression of neutrophil CXCR2, CD11b, and reduced NAD phosphate oxidase components (p22phox, p67phox, and gp91phox) were significantly reduced. Morphological analysis of Hbbth3/+neutrophils showed that a large percentage of mature phenotype neutrophils (Ly6GhiLy6Clow) appeared as band form cells, and a striking expansion of immature (Ly6GlowLy6Clow) hyposegmented neutrophils, consisting mainly of myelocytes and metamyelocytes, was noted. Intriguingly, expression of an essential mediator of neutrophil terminal differentiation, the ets transcription factor PU.1, was significantly decreased in Hbbth3/+neutrophils. In addition, in vivo infection withStreptococcus pneumoniaefailed to induce PU.1 expression or upregulate neutrophil effector functions in Hbbth3/+mice. Similar changes to neutrophil morphology and PU.1 expression were observed in splenectomized and nonsplenectomized HbE/β-thalassemia patients. This study provides a mechanistic insight into defective neutrophil maturation in β-thalassemia patients, which contributes to deficiencies in neutrophil effector functions.
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand.|Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Panjaree
P
Siwaponanan
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Jurre Ynze
JY
Siegers
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Razi
R
Ghazali
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity.
Thian
T
Ng
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Bradley
B
McColl
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, and.
Garrett Zhen-Wei
GZ
Ng
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, and.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; and.
Philip
P
Sutton
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity.
Nancy
N
Wang
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity.
Isabelle
I
Ooi
Department of Pathobiology, Faculty of Science, and.
Chayada
C
Thiengtavor
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand.
Suthat
S
Fucharoen
Department of Pathobiology, Faculty of Science, and.
Pornthip
P
Chaichompoo
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand.|Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
Saovaros
S
Svasti
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity.
Odilia
O
Wijburg
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; and.
Jim
J
Vadolas
D000328:Adult; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D055815:Young Adult; D017086:beta-Thalassemia / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000099232:Proto-Oncogene Protein Spi-1
D039481:CD11b Antigen; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1