IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression

Abstract

Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34+ cells, which account for 0.2% of monocytes in peripheral blood, and ∼ 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34+ cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34+ cells directly responded to LPS stimulation by activating the MAPK and NF-κB signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBPα and C/EBPβ, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.

Regulation of emergency granulopoiesis during infection

“…( 29 ) and Schurch et al ( 86 ) demonstrated that HSPCs and MSC produced IL-6 in response to inflammatory signals that stimulate HSC mobilization and myeloid differentiation in neutropenia or to promote clearance of the infection. More recently, it has been shown that TLR4 signaling-derived IL-6 promotes emergency granulopoiesis by phosphorylating C/EBP-α/β ( 87 ).…”

Molecular cloning, expressional analyses and functional identification of TRAIL in tilapia, Oreochromis niloticus

“…Higher expression of TNFSF10 in the liver was also observed in chickens (Abdalla et al, 2004), mandarin fish (Gao et al, 2008) and Japanese pufferfish (Biswas et al, 2015). As the liver maintains the optimal liver mass/body mass ratio by maintaining a 'dynamic equilibrium' between proliferation and apoptosis in hepatocytes (Fausto et al, 2006), the TNF-induced signalling pathway initiates factor κB (NF-κB) (Barut et al, 2020;Sasaki et al, 2021). The head kidney and spleen are secondary lymphoid organs in teleost fish, and play important roles in fish immunology.…”

“…Lipopolysaccharide and Poly I:C, two kinds of pathogen‐associated molecular patterns, elicit an acute inflammatory response and promote the release of multiple cytokines in leucocytes and macrophages by activating TLR‐related signalling pathways, such as mitogen‐activated protein kinase (MAPK) pathways and nuclear factor κB (NF‐κB) (Barut et al., 2020; Sasaki et al., 2021). The head kidney and spleen are secondary lymphoid organs in teleost fish, and play important roles in fish immunology.…”

Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity

“…C/EBPb and C/EBPa were also found to play key roles in the differentiation of human CD34+ cells towards the myeloid lineage in response to LPS in vitro. In this case, however, LPS activated a TLR4-MD2-MyD88 pathway that resulted in the expression of IL-6, which in turn, induced C/EBPa and C/EBPb phosphorylation, finally promoting monocytic-macrophage differentiation (57). Direct TLR4 triggering of HSCs also plays an important role in the maintenance of HSC fitness.…”