title: Retinoid agonist Am80-enhanced neutrophil bactericidal activity arising from granulopoiesis in vitro and in a neutropenic mouse model.
abstract: Despite advances in the therapeutic use of recombinant granulocyte colony-stimulating factor (G-CSF) to promote granulopoiesis of human hematopoietic stem cells (HSCs), neutropenia remains one of the most serious complications of cancer chemotherapy. We discovered that retinoid agonist Am80 (tamibarotene) is more potent than G-CSF in coordinating neutrophil differentiation and immunity development. Am80-induced neutrophils (AINs) either in vitro or in neutropenic mouse model displayed strong bactericidal activities, similar to those of human peripheral blood neutrophils (PBNs) or mouse peripheral blood neutrophils (MPBNs) but markedly greater than did G-CSF–induced neutrophils (GINs). In contrast to GINs but similar to PBNs, the enhanced bacterial killing by AINs accompanied both better granule maturation and greater coexpression of CD66 antigen with the integrin β2 subunit CD18. Consistently, anti-CD18 antibody neutralized Am80-induced bactericidal activities of AINs. These studies demonstrate that Am80 is more effective than G-CSF in promoting neutrophil differentiation and bactericidal activities, probably through coordinating the functional interaction of CD66 with CD18 to enhance the development of neutrophil immunity during granulopoiesis. Our findings herein suggest a molecular rationale for developing new therapy against neutropenia using Am80 as a cost-effective treatment option.
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA 90027, USA.
authors.forename: Wanjing
authors.initials: W
authors.lastname: Ding
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Rahul
authors.initials: R
authors.lastname: Mittal
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Zhang
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
authors.forename: Lingtao
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001419:Bacteria / Q000187:drug effects / Q000276:immunology; D001565:Benzoates / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003520:Cyclophosphamide; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D012176:Retinoids / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D001565:Benzoates; D018821:CD18 Antigens; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide