Regulation of myelopoiesis by proinflammatory cytokines in infectious diseases

Abstract

Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.

Keywords: Cytokine; Emergency myelopoiesis; Hematopoietic progenitor cell; Hematopoietic stem cell.

Fig. 1

Regulation of myelopoiesis under homeostatic and pathogenic conditions. a Under normal homeostatic hematopoiesis, HSCs reside in the perivascular region of the BM, the so-called BM niche, and MSCs, ECs, and pericytes regulate HSC dormancy and differentiation through cytokines and cell contact–dependent signals such as Notch. b In severe infection, myeloid cells need to be replenished from HSCs and progenitors in BM because of their low proliferative activity, a process called emergency myelopoiesis. HSCs can directly sense the presence of pathogens via pattern recognition receptors such as TLRs and proinflammatory cytokines, and they expand and differentiate into mature myeloid cells to control the infection

Fig. 2

Roles of proinflammatory cytokines in the regulation of myelopoiesis under pathogenic conditions such as infection. a IFN-γ secreted from CTLs directly acts on HSCs, thereby favoring monocytic differentiation. Moreover, IFN-γ stimulates BM MSCs to release IL-6, which promotes monocytopoiesis from MPPs. Bacterial infection activates MPPs through TLRs to release IL-6, which promotes granulopoiesis from MPPs. b IL-27 is a limited unique cytokine directly acting on HSCs to promote differentiation into myeloid progenitors during emergency myelopoiesis. Among various types of hematopoietic cells in the BM, IL-27 predominantly and continuously promotes the expansion of LSK cells only, especially LT-HSCs and MyRPs with long-term repopulating activity, and differentiates them into myeloid progenitors in synergy with SCF. Blood-stage malaria infection induces IFN-γ production from CD4⁺ T cells and NK cells, which may stimulate MSCs to produce IL-27. IL-27 then directly acts on HSCs and promotes the differentiation into myeloid progenitors, resulting in enhanced production of neutrophils to remove malaria-infected RBCs. c HSCs are held within the BM by adhesive interactions and the chemoattraction provided by CXCL12/CXCR4 signaling. G-CSF triggers the expansion of neutrophils and their precursors, creating a proteolytic environment leading to the degradation of adhesive interactions between chemokines and their receptors. Bacteria and their fragments stimulate TLR-expressing ECs but not HSPCs and consequently produce large amounts of G-CSF, which promotes enhanced proliferation of HSPCs and differentiation into neutrophils

Fig. 3

Role of IL-27 in hematopoiesis. LT-HSCs have the capacity to self-renew over the entire life span, and they give rise to all cell types of the BM and peripheral blood. Other pluripotent progenitors (e.g., short-term repopulating HSCs and MPPs) have less self-renewal capacity. Together, these cell types mainly constitute the HSPC population. MPPs are thought to differentiate into the two main branches of hematopoietic development that are the common lymphoid progenitor (CLP) and the common myeloid progenitor (CMP). IL-27 directly activates LT-HSCs and MyRPs with long-term repopulating activity together with SCF and promotes the differentiation into the myeloid progenitors, M-CSFR⁺Flt3⁻CD16/32⁺ LSKs. CDP, common DC progenitor; GMP, granulocyte and macrophage progenitor; MDP, macrophage DC progenitor; MEP, megakaryocyte and erythrocyte progenitor

Fig. 4

Promotion of emergency myelopoiesis during blood-stage malaria infection by IL-27. In the blood stage of malaria infection model with the attenuated variant P. berghei XAT derived from the lethal strain P. berghei NK65, IFN-γ production induced by IL-12 and phagocytic cells in the spleen play critical roles in controlling parasitemia to remove infected RBCs. The malaria infection induces splenomegaly and extramedullary hematopoiesis by augmenting IL-27 expression in the BM and spleen via enhanced production of IFN-γ from T cells and NK cells. IL-27 then directly acts on HSCs and promotes their expansion and differentiation into myeloid progenitors together with SCF, resulting in increased production of neutrophils to control the malaria infection. Thus, IL-27 is a novel cytokine that directly acts on HSCs and promotes emergency myelopoiesis