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

作者：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^*

来源：EMBO Molecular Medicine, 2016, 8(11): 1340-1359.

DOI：10.15252/emmm.201606434

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

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 (RAR), 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 RAR(2,)C/EBP epsilon, 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.

• 出版日期2016-11
• 单位浙江大学