TY - JOUR
T1 - Reduced PU.1 expression underlies aberrant neutrophil maturation and function in b-Thalassemia mice and patients
AU - Siwaponanan, Panjaree
AU - Siegers, Jurre Ynze
AU - Ghazali, Razi
AU - Ng, Thian
AU - Mccoll, Bradley
AU - Ng, Garrett Zhen Wei
AU - Sutton, Philip
AU - Wang, Nancy
AU - Ooi, Isabelle
AU - Thiengtavor, Chayada
AU - Fucharoen, Suthat
AU - Chaichompoo, Pornthip
AU - Svasti, Saovaros
AU - Wijburg, Odilia
AU - Vadolas, Jim
PY - 2017/6/8
Y1 - 2017/6/8
N2 - 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 Hbbth3/1 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 Hbbth3/1 mice, the expression of neutrophil CXCR2, CD11b, and reduced NAD phosphate oxidase components (p22phox, p67phox, and gp91phox) were significantly reduced.Morphological analysis of Hbbth3/1 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 Hbbth3/1 neutrophils. In addition, in vivo infection with Streptococcus pneumoniae failed to induce PU.1 expression or upregulate neutrophil effector functions in Hbbth3/1 mice. Similar changes to neutrophil morphology and PU.1 expression were observed in splenectomized and nonsplenectomized HbE/β-Thalassemia patients. This study provides amechanistic insight into defective neutrophil maturation in β-Thalassemia patients, which contributes to deficiencies in neutrophil effector functions.
AB - 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 Hbbth3/1 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 Hbbth3/1 mice, the expression of neutrophil CXCR2, CD11b, and reduced NAD phosphate oxidase components (p22phox, p67phox, and gp91phox) were significantly reduced.Morphological analysis of Hbbth3/1 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 Hbbth3/1 neutrophils. In addition, in vivo infection with Streptococcus pneumoniae failed to induce PU.1 expression or upregulate neutrophil effector functions in Hbbth3/1 mice. Similar changes to neutrophil morphology and PU.1 expression were observed in splenectomized and nonsplenectomized HbE/β-Thalassemia patients. This study provides amechanistic insight into defective neutrophil maturation in β-Thalassemia patients, which contributes to deficiencies in neutrophil effector functions.
UR - http://www.scopus.com/inward/record.url?scp=85020704965&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-07-730135
DO - 10.1182/blood-2016-07-730135
M3 - Article
C2 - 28325862
AN - SCOPUS:85020704965
SN - 0006-4971
VL - 129
SP - 3087
EP - 3099
JO - Blood
JF - Blood
IS - 23
ER -