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.
T.C. is supported by grants from the Ministry of Science and Technology of China (2016YFA0100600), the National Natural Science Foundation of China (81421002), and the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2016-I2M-1-017). Y.X. is supported by grants from the National Basic Research Program of China (2015CB964903), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-12M-1-003), and Chinese National Natural Science Foundation (31471116). P.L. is supported by a grant from the Chinese National Natural Science Foundation (81600083), the Peking Union Medical College Youth Fund, and the Fundamental Research Funds for the Central Universities (3332015184). H.R.L. is supported by National Institutes of Health Grants R01AI103142, R01HL092020, and P01 HL095489 and by a grant from Flight Attendant Medical Research Institute.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- acute lung injury
- bronchoalveolar lavage fluid
- bone marrow
- BM-derived mononuclear cell
- granulocyte CFU
- granulocyte/monocyte CFU
- monocyte CFU
- chronic granulomatous disease
- common myeloid progenitor
- granulocyte-monocyte progenitor
- hematopoietic stem cell
- megakaryocyte/erythroid progenitor
- N-acetyl cysteine
- phagocytic NADPH oxidase
- Peroxy Orange 1
- phosphatase and tensin homolog
- reactive oxygen species
- Received November 28, 2016.
- Accepted January 24, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.