Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality

Lin Li, Xiaotian Qi, Weili Sun, Hisham Abdel-Azim, Siyue Lou, Hong Zhu, Nemani V. Prasadarao, Alice Zhou, Hiroyuki Shimada, Koichi Shudo, Yong Mi Kim, Sajad Khazal, Qiaojun He, David Warburton, Lingtao Wu

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Neutrophils generated by granulocyte colony-stimulating factor (GCSF) are functionally immature and, consequently, cannot effectively reduce infection and infection-related mortality in cancer chemotherapy-induced neutropenia (CCIN). Am80, a retinoic acid (RA) agonist that enhances granulocytic differentiation by selectively activating transcription factor RA receptor alpha (RARα), alternatively promotes RA-target gene expression. We found that in normal and malignant primary human hematopoietic specimens, Am80-GCSF combination coordinated proliferation with differentiation to develop complement receptor-3 (CR3)-dependent neutrophil innate immunity, through altering transcription of RA-target genes RARβ2, C/EBPε, CD66, CD11b, and CD18. This led to generation of functional neutrophils capable of fighting infection, whereas neutralizing neutrophil innate immunity with anti-CD18 antibody abolished neutrophil bactericidal activities induced by Am80-GCSF. Further, Am80-GCSF synergy was evaluated using six different dose-schedule-infection mouse CCIN models. The data demonstrated that during “emergency” granulopoiesis in CCIN mice undergoing transient systemic intravenous bacterial infection, Am80 effect on differentiating granulocytic precursors synergized with GCSF-dependent myeloid expansion, resulting in large amounts of functional neutrophils that reduced infection. Importantly, extensive survival tests covering a full cycle of mouse CCIN with perpetual systemic intravenous bacterial infection proved that without causing myeloid overexpansion, Am80-GCSF generated sufficient numbers of functional neutrophils that significantly reduced infection-related mortality in CCIN mice. These findings reveal a differential mechanism for generating functional neutrophils to reduce CCIN-associated infection and mortality, providing a rationale for future therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)1340-1359
Number of pages20
JournalEMBO Molecular Medicine
Volume8
Issue number11
DOIs
StatePublished - Nov 1 2016

Keywords

  • functional neutrophils
  • innate immunity
  • myeloid expansion
  • neutrophil bactericidal activity
  • neutrophil differentiation

ASJC Scopus subject areas

  • Molecular Medicine

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    Li, L., Qi, X., Sun, W., Abdel-Azim, H., Lou, S., Zhu, H., Prasadarao, N. V., Zhou, A., Shimada, H., Shudo, K., Kim, Y. M., Khazal, S., He, Q., Warburton, D., & Wu, L. (2016). Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality. EMBO Molecular Medicine, 8(11), 1340-1359. https://doi.org/10.15252/emmm.201606434