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 Citations (Scopus)

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
Externally publishedYes

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Granulocyte Colony-Stimulating Factor
Neutropenia
Neutrophils
Infection
Drug Therapy
Tretinoin
Neoplasms
Bacterial Infections
Innate Immunity
Mortality
Activating Transcription Factors
Macrophage-1 Antigen
tamibarotene
Anti-Idiotypic Antibodies
Appointments and Schedules
Emergencies
Gene Expression
Survival
Genes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality. / Li, Lin; Qi, Xiaotian; Sun, Weili; Abdel-Azim, Hisham; Lou, Siyue; Zhu, Hong; Prasadarao, Nemani V.; Zhou, Alice; Shimada, Hiroyuki; Shudo, Koichi; Kim, Yong Mi; Khazal, Sajad; He, Qiaojun; Warburton, David; Wu, Lingtao.

In: EMBO Molecular Medicine, Vol. 8, No. 11, 01.11.2016, p. 1340-1359.

Research output: Contribution to journalArticle

Li, L, Qi, X, Sun, W, Abdel-Azim, H, Lou, S, Zhu, H, Prasadarao, NV, Zhou, A, Shimada, H, Shudo, K, Kim, YM, 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, vol. 8, no. 11, pp. 1340-1359. https://doi.org/10.15252/emmm.201606434
Li, Lin ; Qi, Xiaotian ; Sun, Weili ; Abdel-Azim, Hisham ; Lou, Siyue ; Zhu, Hong ; Prasadarao, Nemani V. ; Zhou, Alice ; Shimada, Hiroyuki ; Shudo, Koichi ; Kim, Yong Mi ; Khazal, Sajad ; He, Qiaojun ; Warburton, David ; Wu, Lingtao. / Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality. In: EMBO Molecular Medicine. 2016 ; Vol. 8, No. 11. pp. 1340-1359.
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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.",
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AU - Li, Lin

AU - Qi, Xiaotian

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AU - Abdel-Azim, Hisham

AU - Lou, Siyue

AU - Zhu, Hong

AU - Prasadarao, Nemani V.

AU - Zhou, Alice

AU - Shimada, Hiroyuki

AU - Shudo, Koichi

AU - Kim, Yong Mi

AU - Khazal, Sajad

AU - He, Qiaojun

AU - Warburton, David

AU - Wu, Lingtao

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