title: Reactive Oxygen Species-Producing Myeloid Cells Act as a Bone Marrow Niche for Sterile Inflammation-Induced Reactive Granulopoiesis.
abstract: Both microbial infection and sterile inflammation augment bone marrow (BM) neutrophil production, but whether the induced accelerated granulopoiesis is mediated by a common pathway and the nature of such a pathway are poorly defined. We recently established that BM myeloid cell-derived reactive oxygen species (ROS) externally regulate myeloid progenitor proliferation and differentiation in bacteria-elicited emergency granulopoiesis. In this article, we show that BM ROS levels are also elevated during sterile inflammation. Similar to in microbial infection, ROS were mainly generated by the phagocytic NADPH oxidase in Gr1+myeloid cells. The myeloid cells and their ROS were uniformly distributed in the BM when visualized by multiphoton intravital microscopy, and ROS production was both required and sufficient for sterile inflammation-elicited reactive granulopoiesis. Elevated granulopoiesis was mediated by ROS-induced phosphatase and tensin homolog oxidation and deactivation, leading to upregulated PtdIns(3,4,5)P3 signaling and increased progenitor cell proliferation. Collectively, these results demonstrate that, although infection-induced emergency granulopoiesis and sterile inflammation-elicited reactive granulopoiesis are triggered by different stimuli and are mediated by distinct upstream signals, the pathways converge to NADPH oxidase-dependent ROS production by BM myeloid cells. Thus, BM Gr1+myeloid cells represent a key hematopoietic niche that supports accelerated granulopoiesis in infective and sterile inflammation. This niche may be an excellent target in various immune-mediated pathologies or immune reconstitution after BM transplantation.
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Hyun-Jeong
authors.identifier: 0000-0001-7070-6066
authors.initials: HJ
authors.lastname: Kwak
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Besnik
authors.initials: B
authors.lastname: Bajrami
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yuanfu
authors.identifier: 0000-0003-0576-3907
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Shin-Young
authors.identifier: 0000-0001-6385-4132
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Cesar
authors.initials: C
authors.lastname: Nombela-Arrieta
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Subhanjan
authors.identifier: 0000-0002-4852-0369
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kambara
authors.affiliation: Department of Hematopathology, VA Boston Healthcare System, West Roxbury, MA 02132.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 and.|Joint Program in Transfusion Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Li
authors.initials: L
authors.lastname: Chai
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Tao
authors.identifier: 0000-0003-4395-1095
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115; Hongbo.Luo@childrens.harvard.edu.
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D042381:Granulocyte Precursor Cells / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006410:Hematopoiesis / Q000276:immunology* / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species