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.

Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection

“…The observed increase in macrophage and monocyte numbers in infected mice is due at least in part to proliferation and recruitment of progenitor cells from the bone marrow [16,17], but it also might involve local proliferation of monocytes and/or macrophages in the tissues, as has been documented in helminth infection [6]. To test whether differentiated myeloid cells proliferate locally during P .…”

“…In mouse models employing rodent-adapted parasites, myeloid expansion has been shown to involve IL-27-dependent proliferation of hematopoietic stem cells in the bone marrow [16] and interferon gamma (IFN-γ)-dependent mobilization of multipotent myeloid progenitor cells into the spleen [5,17], where they can give rise to monocytes and, presumably, macrophages. However, the cells and cytokines that regulate differentiation and proliferation downstream of these early progenitor stages remain undefined.…”

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

“…Hematopoietic stem cells express both IL-27R subunits, such as WSX-1 and gp130 (41). IL-27 was recently revealed to directly act on hematopoietic stem cells and promote their expansion and differentiation to myeloid progenitor cells in vitro and in vivo in synergy with stem cell factor (42). In addition, it was demonstrated that IL-27 plays an important role in the control of infection with Plasmodium berghei -attenuated variant XAT.…”

“…In addition, it was demonstrated that IL-27 plays an important role in the control of infection with Plasmodium berghei -attenuated variant XAT. IL-27, which is produced through IFN-γ production during malaria infection, promotes expansion and differentiation of hematopoietic stem cells to myeloid progenitors and mobilizes them into the spleen, resulting in enhanced myelopoiesis with increased numbers of mature myeloid cells such as neutrophils (42). Thus, IL-27 is one of the limited unique cytokines directly acting on hematopoietic stem cells and promoting their expansion and differentiation into myeloid progenitor cells.…”

Inflammation Shapes Stem Cells and Stemness during Infection and Beyond

“…Inflammation-induced myelopoiesis, due to pathogen presence, results in the release of interleukin-27 causing activation and differentiation of hematopoietic stem cells (HSCs) (Furusawa et al, 2016). Chronic infection, as seen in the presence of the Mycobacterium avium , results in the activation of quiescent HSCs through the release of the inflammatory mediator interferon-γ (Baldridge et al, 2010).…”