The pro-Inflammatory cytokines effects on mobilization, self-renewal and differentiation of hematopoietic stem cells

Jahandideh, Bahman; Derakhshani, Mehdi; Abbaszadeh, Hossein; Movassaghpour, Ali Akbar; Mehdizadeh, Amir; Talebi, Mehdi; Yousefi, Mehdi

doi:10.1016/j.humimm.2020.01.004

Cited by 32 publications

(24 citation statements)

References 130 publications

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“…[ 8 , 9 , 32 ] Numerous reports have noted that long‐term stimulation with pro‐inflammatory cytokines causes functional exhaustion of HSCs. [ 6 , 8 , 9 , 33 , 34 , 35 ] Moreover, continuously activated TLR2 or TLR4 signaling increase the number of HSCs. In our research, long‐term activation of TLR9 signaling increased the abundance of HSCs, accompanied by a decreased capacity of colony formation.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, under stimuli, TLR9 activates downstream signaling pathways and lead to production of inflammatory cytokines in immune effector cells. [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] However, we found that levels of type I, type II interferon, TNF‐ α , IL‐1 β , and IL‐6 in bone marrow cavity of Irf8 −/− mice changed little following exposure to CpG. This observation is consistent with a previous report wherein IFN α was undetectable in serum following CpG stimulation in Irf8 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Zhang

Qiu

et al. 2021

Advanced Science

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IRF8 is a key regulator of innate immunity receptor signaling and plays diverse functions in the development of hematopoietic cells. The effects of IRF8 on hematopoietic stem cells (HSCs) are still unknown. Here, it is demonstrated that IRF8 deficiency results in a decreased number of long-term HSCs (LT-HSCs) in mice. However, the repopulation capacity of individual HSCs is significantly increased. Transcriptomic analysis shows that IFN-and IFNsignaling is downregulated in IRF8-deficient HSCs, while their response to proinflammatory cytokines is unchanged ex vivo. Further tests show that Irf8 −/− HSCs can not respond to CpG, an agonist of Toll-like receptor 9 (TLR9) in mice, while long-term CpG stimulation increases wild-type HSC abundance and decreases their bone marrow colony-forming capacity. Mechanistically, as the primary producer of proinflammatory cytokines in response to CpG stimulation, dendritic cells has a blocked TLR9 signaling due to developmental defect in Irf8 −/− mice. Macrophages remain functionally intact but severely reduce in Irf8 −/− mice. In NK cells, IRF8 directly regulates the expression of Tlr9 and its deficiency leads to no increased IFN production upon CpG stimulation. These results indicate that IRF8 regulates HSCs, at least in part, through controlling TLR9 signaling in diverse innate immune cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Zhang

Qiu

et al. 2021

Advanced Science

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“…We speculate that reduced leukocyte counts are possibly due to the ability of Mn porphyrins to decrease inflammatory markers, 58,59 as proinflammatory cytokines can increase myelopoiesis. 60,61 Neutrophils are in an activated state in SCD, and high baseline leukocyte numbers are associated with increased morbidity and mortality in SCD. 44 Furthermore, the substantial levels of oxidative stress in SSRBCs enhance HbS autoxidation, which could contribute to cell membrane damage, premature erythrocyte aging, and hemolysis.…”

Section: Discussionmentioning

confidence: 99%

Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo

Thamilarasan¹,

Estupinan²,

Batinić‐Haberle

et al. 2020

Blood Advances

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In sickle cell disease (SCD), adhesion of sickle red blood cells (SSRBCs) and activated leukocytes in inflamed venules affects blood rheology, causing vaso-occlusive manifestations and vital reduction in microvascular blood flow. Recently, we found that NADPH oxidases (NOXs) create a vicious feedback loop within SSRBCs. This positive feedback loop mediates SSRBC adhesion to the endothelium. We show for the first time the therapeutic effectiveness of the redox-active manganese (Mn) porphyrins MnTnBuOE-2-PyP5+ (MnBuOE; BMX-001) and MnTE-2-PyP5+ (MnE; BMX-010, AEOL10113) to treat established vaso-occlusion in a humanized sickle mouse model of an acute vaso-occlusive crisis using intravital microscopy. These Mn porphyrins can suppress SSRBC NOX activity. Subcutaneous administration of only 1 dose of MnBuOE or MnE at 0.1 to 2 mg/kg after the inflammatory trigger of vaso-occlusion, or simultaneously, reversed and reduced leukocyte and SSRBC adhesion, diminished leukocyte rolling, restored blood flow, and increased survival rate. Furthermore, MnBuOE and MnE administered to sickle mice subcutaneously at 0.1 to 1 mg/kg for 28 days (except on weekends) did not exacerbate anemia, which seemed to be due to downregulation of both SSRBC reactive oxygen species production and exposure of the eryptotic marker phosphatidylserine. In addition, Mn porphyrins ameliorated leukocytosis, venous blood gases, endothelial activation, and organ oxidative damage. Our data suggest that Mn porphyrins, likely by repressing NOX-mediated adhesive function of SSRBCs and activated leukocytes, could represent a novel, safe therapeutic intervention to treat or prevent the establishment of acute pain crises. These NOX-targeted antioxidants merit further assessment in SCD clinical trials.

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“…The short half-life of the circulating neutrophils together with the continuous replenishment of neutrophils from the bone-marrow, leads to constant dynamic changes in the neutrophil population. In addition, exposure to different combinations of cytokines and chemokines modulates not only the activation state of the mature neutrophils but also normal and emergency granulopoiesis [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Sionov

2021

Cells

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Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

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The pro-Inflammatory cytokines effects on mobilization, self-renewal and differentiation of hematopoietic stem cells

Cited by 32 publications

References 130 publications

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

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