title: Promotion of Expansion and Differentiation of Hematopoietic Stem Cells by Interleukin-27 into Myeloid Progenitors to Control Infection in Emergency Myelopoiesis.
abstract: Emergency myelopoiesis is inflammation-induced hematopoiesis to replenish myeloid cells in the periphery, which is critical to control the infection with pathogens. Previously, pro-inflammatory cytokines such as interferon (IFN)-α and IFN-γ were demonstrated to play a critical role in the expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, leading to production of mature myeloid cells, although their inhibitory effects on hematopoiesis were also reported. Therefore, the molecular mechanism of emergency myelopoiesis during infection remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in the emergency myelopoiesis. Among various types of hematopoietic cells in bone marrow, IL-27 predominantly and continuously promoted the expansion of only Lineage-Sca-1+c-Kit+ (LSK) cells, especially long-term repopulating HSCs and myeloid-restricted progenitor cells with long-term repopulating activity, and the differentiation into myeloid progenitors in synergy with stem cell factor. These progenitors expressed myeloid transcription factors such as Spi1, Gfi1, and Cebpa/b through activation of signal transducer and activator of transcription 1 and 3, and had enhanced potential to differentiate into migratory dendritic cells (DCs), neutrophils, and mast cells, and less so into macrophages, and basophils, but not into plasmacytoid DCs, conventional DCs, T cells, and B cells. Among various cytokines, IL-27 in synergy with the stem cell factor had the strongest ability to augment the expansion of LSK cells and their differentiation into myeloid progenitors retaining the LSK phenotype over a long period of time. The experiments using mice deficient for one of IL-27 receptor subunits, WSX-1, and IFN-γ revealed that the blood stage of malaria infection enhanced IL-27 expression through IFN-γ production, and the IL-27 then promoted the expansion of LSK cells, differentiating and mobilizing them into spleen, resulting in enhanced production of neutrophils to control the infection. Thus, IL-27 is one of the limited unique cytokines directly acting on HSCs to promote differentiation into myeloid progenitors during emergency myelopoiesis.
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Furusawa
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Izuru
authors.initials: I
authors.lastname: Mizoguchi
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yukino
authors.initials: Y
authors.lastname: Chiba
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hisada
authors.affiliation: Department of Infectious Diseases, Kyorin University of Medicine, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Kobayashi
authors.affiliation: Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuchida
authors.affiliation: Department of Microbiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Ema
authors.affiliation: Department of Immunology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D001853:Bone Marrow / Q000502:physiology; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000502:physiology; D038042:Myelopoiesis / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000502:physiology
chemical_list: D016207:Cytokines; C486767:Il27 protein, mouse; D007378:Interleukins