Reduced PU.1 expression underlies aberrant neutrophil maturation and function in β-thalassemia mice and patients

Panjaree Siwaponanan, Jurre Ynze Siegers, Razi Ghazali, Thian Ng, Bradley McColl, Garrett Zhen-Wei Ng, Philip Sutton, Nancy Wang, Isabelle Ooi, Chayada Thiengtavor, Suthat Fucharoen, Pornthip Chaichompoo, Saovaros Svasti, Odilia Wijburg and Jim Vadolas

Key Points

  • Aberrant neutrophil maturation is associated with reduced effector functions in β-thalassemia.

  • PU.1, the key regulator of terminal neutrophil maturation, is dysregulated in β-thalassemia.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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 with Streptococcus pneumoniae failed 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.

  • Submitted July 25, 2016.
  • Accepted February 28, 2017.
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