scholarly journals Toll-like receptor signaling-deficient mice are easy mobilizers: evidence that TLR signaling prevents mobilization of hematopoietic stem/progenitor cells in HO-1-dependent manner

Leukemia ◽  
2016 ◽  
Vol 30 (12) ◽  
pp. 2416-2419 ◽  
Author(s):  
M Adamiak ◽  
A Abdelbaset-Ismail ◽  
M Kucia ◽  
J Ratajczak ◽  
M Z Ratajczak
Keyword(s):  
Progenitor Cells ◽  
Dependent Manner ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Hematopoietic Stem ◽  
Deficient Mice

scholarly journals Dectin-1 Stimulation of Hematopoietic Stem and Progenitor Cells Occurs In Vivo and Promotes Differentiation Toward Trained Macrophages via an Indirect Cell-Autonomous Mechanism

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Cristina Bono ◽  
Alba Martínez ◽  
Javier Megías ◽  
Daniel Gozalbo ◽  
Alberto Yáñez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Progenitor Cells ◽  
Recipient Mouse ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Hematopoietic Stem ◽  
Content Type ◽  
Stem And Progenitor Cells

ABSTRACT Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage. In this study, we used an HSPC transplantation model to investigate the possible direct interaction of β-glucan and its receptor (dectin-1) on HSPCs in vivo. Purified HSPCs from bone marrow of B6Ly5.1 mice (CD45.1 alloantigen) were transplanted into dectin-1−/− mice (CD45.2 alloantigen), which were then injected with β-glucan (depleted zymosan). As recipient mouse cells do not recognize the dectin-1 agonist injected, interference by soluble mediators secreted by recipient cells is negligible. Transplanted HSPCs differentiated into macrophages in response to depleted zymosan in the spleens and bone marrow of recipient mice. Functionally, macrophages derived from HSPCs exposed to depleted zymosan in vivo produced higher levels of inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 6 [IL-6]). These results demonstrate that trained immune responses, already described for monocytes and macrophages, also take place in HSPCs. Using a similar in vivo model of HSPC transplantation, we demonstrated that inactivated yeasts of Candida albicans induce differentiation of HSPCs through a dectin-1- and MyD88-dependent pathway. Soluble factors produced following exposure of HSPCs to dectin-1 agonists acted in a paracrine manner to induce myeloid differentiation and to influence the function of macrophages derived from dectin-1-unresponsive or β-glucan-unexposed HSPCs. Finally, we demonstrated that an in vitro transient exposure of HSPCs to live C. albicans cells, prior to differentiation, is sufficient to induce a trained phenotype of the macrophages they produce in a dectin-1- and Toll-like receptor 2 (TLR2)-dependent manner. IMPORTANCE Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections. Understanding host defense is essential to design novel therapeutic strategies to boost immune protection against Candida albicans. In this article, we delve into two new concepts that have arisen over the last years: (i) the delivery of myelopoiesis-inducing signals by microbial components directly sensed by hematopoietic stem and progenitor cells (HSPCs) and (ii) the concept of “trained innate immunity” that may also apply to HSPCs. We demonstrate that dectin-1 ligation in vivo activates HSPCs and induces their differentiation to trained macrophages by a cell-autonomous indirect mechanism. This points to new mechanisms by which pathogen detection by HSPCs may modulate hematopoiesis in real time to generate myeloid cells better prepared to deal with the infection. Manipulation of this process may help to boost the innate immune response during candidiasis.

The Role of C5a in the Mobilization of Hematopoietic Stem/Progenitor Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3472-3472
Author(s):  
Ali Jalili ◽  
Neeta Shirvaikar ◽  
Chris Korol ◽  
Anna Janowska-Wieczorek
Keyword(s):  
Steady State ◽  
Progenitor Cells ◽  
Complement System ◽  
Cxcr4 Expression ◽  
Classical Pathway ◽  
Dependent Manner ◽  
C5a Receptor ◽  
Hematopoietic Stem ◽  
The Complement System ◽  
Deficient Mice

Abstract The complement system, a vital component of the immune system, has been shown to play a role in hematopoietic stem/progenitor cell (HSPC) trafficking. C3a is known to be important in the retention of HSPC in the bone marrow (BM) as C3a-deficient mice are good mobilizers, and C5a is important in the mobilization of HSPC because C5a-deficient mice are poor mobilizers (Stem Cells2007; 25: 3093). Further, granulocyte-colony stimulating factor (G-CSF) activates the complement system via the classical pathway, down-regulates stromal-derived factor (SDF)-1 in BM stromal cells and decreases expression of its receptor, CXCR4, in myeloid cells. In this work investigated the mechanism of C5a involvement in HSPC mobilization. Using RT-PCR and FACS we examined the expression of the C5a receptor (CD88) on mobilized peripheral blood (PB) and steady-state PB HSPC and mature white blood cells, and in vitro-expanded myeloid, erythroid, and megakaryocytic progenitor cells. We found that CD88, like the G-CSF receptor, is not expressed on BM, PB or cord blood HSPC (CD34+ cells); during CD34+ cell differentiation the expression of CD88 increases in myelocytic and megakaryocytic progenitors; and the percentage of monocytes and polymorphonuclear (PMN) cells expressing CD88 is significantly higher in mobilized than in steady-state PB. Examing the function of C5a (using flow cytometry) we found that, unlike C3a, C5a decreases CXCR4 expression in a dose-dependent manner in monocytes and PMN, but not in lymphocytes; and this effect was not seen when anti-C5a antibody was added. Interestingly, we found that G-CSF down-regulation of CXCR4 expression on PMN was partially restored by anti-C5a antibody, suggesting that the mobilizing effects of G-CSF are at least in part due to the action of C5a. Moreover, chemotaxis of PMN towards SDF-1 (chemotaxis assay) increased when these cells were stimulated with C3a but decreased with both C5a and G-CSF, reflecting the CXCR4 expression status of these cells after stimulation. We also examined the effect of C5a on matrix metalloproteinase (MMP) secretion in BM leukocytes and found that, like G-CSF, C5a increased MMP-9 and MMP-2 secretion into media (zymography). Since the SDF-1/CXCR4 axis plays an integral role in the retention of HSPC in the BM, we conclude that C5a promotes mobilization by disrupting this axis, as well as increasing MMP-9 and MMP-2 secretion by BM leukocytes, thereby allowing egress of HSPC into the PB.

Homeostatic Role of the Krüppel-Like Factor 4 (KLF4) in Proliferation and Differentiation of Primitive Hematopoietic Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1497-1497 ◽  
Author(s):  
Chun Shik Park ◽  
Takeshi Yamada ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Proliferative Potential ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Deficient Mice

Abstract Abstract 1497 Poster Board I-520 KLF4 is a tumor suppressor in the gastrointestinal tract known to induce cell cycle arrest in a cell context dependent manner. We recently reported that KLF4 maintains quiescence of T lymphocytes downstream of T-cell receptor signaling (Yamada et al., Nature Immunology, 2009). The role of KLF4 in reprogramming adult somatic cells into pluripotent stem cells along with Oct3/4, c-Myc and Sox2 suggests that KLF4 restricts proliferation of undifferentiated cells. In spite of a redundant role of KLF4 in fetal liver hematopoietic stem cells (HSC), its role in the maintenance of adult bone marrow HSCs has not been studied yet. To study the role of KLF4 in the hematopoietic system we used gain- and loss-of-function mouse models. Retroviral transfer of KLF4 into wild type bone marrow (BM) cells led to significant reduction of colony forming units (CFU) in methylcellulose cultures due to increased apoptosis and lower proliferation. Then, Mx1-Cre was used to induce deletion of Klf4-floxed mice by polyI:C administration. Analysis of peripheral blood cells up to 6-9 months post polyI:C administration showed significant reduction of monocytes, as previously reported, and expansion of CD8+CD44+ T cells due to their increased proliferative potential. BM cells from Klf4-deficient mice exhibited increased number of myeloid progenitor cells measured by flow cytometry (Lin-Sca-1-c-kit+FcRII/III+CD34+ cells), CFU and CFU-S8. Cytoablation with 5-fluorouracil (5-FU) showed lower nadir of peripheral white blood cells in Klf4-deficient mice compared to control mice. In spite of normal multilineage reconstitution in BM transplants experiments, competitive reconstitution with Klf4-deficient and normal BM cells resulted in reduced contribution of Klf4-deficient cells to peripheral blood, likely due to homing and proliferative differences. Collectively, our data shows that KLF4 has an important role in function of hematopoietic stem and progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome–caspase-1-mediated trafficking of hematopoietic stem/progenitor cells

Leukemia ◽  
2021 ◽  
Author(s):  
Arjun Thapa ◽  
Mateusz Adamiak ◽  
Kamila Bujko ◽  
Janina Ratajczak ◽  
Ahmed K. Abdel-Latif ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Nlrp3 Inflammasome ◽  
Sterile Inflammation ◽  
Dependent Manner ◽  
Proteolytic Activation ◽  
Hematopoietic Stem ◽  
Caspase 1 ◽  
Molecular Pattern ◽  
First Time ◽  
Deficient Mice

AbstractLike their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome–caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.

Novel Evidence That Hematopoietic Stem/Progenitor Cells (HSPCs) Are Mobilized During Hemolysis in an Erythrocyte Lysis-Derived, Sphingosine-1-Phosphate (S1P)-Dependent manner—the Crucial Involvement of Complement Cascade (CC) Activation and Attenuation of CXCR4 Retention Signaling

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3189-3189
Author(s):  
Kasia Mierzejewska ◽  
Magdalena Kucia ◽  
Janina Ratajczak ◽  
Mariusz Z Ratajczak
Keyword(s):  
Progenitor Cells ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Molecular Mechanisms ◽  
Distal Part ◽  
Complement Cascade ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Sphingosine 1 Phosphate ◽  
Deficient Mice ◽  
Chemotactic Gradient

Abstract Abstract 3189 Background. Hemolytic syndromes, such as sickle cell anemia and paroxysmal nocturnal hemoglobinuria, are characterized by an increased number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB). However, the molecular mechanisms responsible for this effect are unclear. In our previous work we have demonstrated that sphingosine-1-phosphate (S1P) released from lysed erythrocytes and activated platelets is a strong chemottractant for bone marrow (BM)-residing HSPCs (Leukemia 2010;24:976–85). Hypothesis. We hypothesized that S1P released from lysed erythrocytes is a major factor responsible for egress of HSPCs from BM into PB in hemolytic syndromes. Experimental approach. To test this hypothesis, normal mice were injected with phenylhydrazine (PHZ), a compound known to induce hemolysis, and we evaluated the number of Sca-1+Kit+Lin– (SKL) HSPCs circulating in PB as well as the number of clonogenic CFU-GM progenitors mobilized into PB. In parallel, we evaluated the blood plasma levels of S1P and stromal derived factor-1 (SDF-1) by sensitive ELISA, the free hemoglobin (Hb) level, as well as complement cascade (CC) activation by measuring the C5b-C9 (membrane attack complex, MAC) level. In some of the experiments, we combined PZH treatment with injection of the CXCR4 antagonist AMD3100. To better assess the role of CC activation, we also performed mobilization in C5-deficient mice, which do not activate the distal part of the CC and thus do not generate C5b-C9/MAC. Results. We found that hemolysis increases the PB plasma level of S1P but does not affect the SDF-1 level. Furthermore, while PHZ-induced hemolysis mobilizes HSPCs into PB with a peak at 6 h after infusion, this mobilization effect is significantly potentiated by administration of AMD3100, which attenuates CXCR4–SDF-1-mediated retention of HSPCs in the BM microenvironment. Of note, PHZ-induced hemolysis together with AMD3100 mobilized twice as many HSPCs as AMD3100 alone. The degree of mobilization of HSPCs correlated with the free Hb level in plasma and activation of the CC (by an increase in MAC level), and, more importantly, mobilization was not seen in C5-deficient mice. Conclusions. We confirmed our previous observation that with the steady-state S1P level, the PB has already established a strong chemotactic gradient for BM-residing HSPCs (Leukemia 2010;24:976–85), which are actively retained in BM niches in a CXCR4–SDF-1-dependent manner. Hemolysis alone, even if it elevates the S1P level in PB significantly, requires two important events i) attenuation of CXCR4–SDF-1 axis-mediated retention in BM niches and ii) simultaneous activation of the CC, which is crucial for induction of permeabilization of the BM–PB barrier. Furthermore, our data also support the notion that the S1P but not the SDF-1 level in PB establishes the critical chemotactic gradient for HSPCs and is responsible for egress of these cells. Based on the observation that C5-deficient mice are poor mobilizers, inactivation of the distal part of the CC should be considered as a therapeutic approach, not only in paroxysmal nocturnal hemoglobinuria but also in other hemolytic syndromes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses

2016 ◽  
Vol 214 (1) ◽  
pp. 227-244 ◽  
Author(s):  
Andreas Westphal ◽  
Weijia Cheng ◽  
Jinbo Yu ◽  
Guntram Grassl ◽  
Martina Krautkrämer ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Membrane Trafficking ◽  
Inflammatory Responses ◽  
Functional Integration ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Lysosomal Trafficking ◽  
Phagosomal Maturation ◽  
Chediak Higashi Syndrome

Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)– and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock. Mechanistic analysis revealed that Lyst specifically controls TLR3- and TLR4-induced endosomal TRIF (TIR domain–containing adapter-inducing interferon β) signaling pathways. Loss of functional Lyst leads to dysregulated phagosomal maturation, resulting in a failure to form an activation-induced Rab7+ endosomal/phagosomal compartment. This specific Rab7+ compartment was further demonstrated to serve as a major site for active TRIF signaling events, thus linking phagosomal maturation to specific TLR signaling pathways. The immunoregulatory role of Lyst on TLR signaling pathways was confirmed in human cells by CRISPR/Cas9-mediated gene inactivation. As mutations in LYST cause human Chédiak-Higashi syndrome, a severe immunodeficiency, our findings also contribute to a better understanding of human disease mechanisms.

scholarly journals Infection Mobilizes Hematopoietic Stem Cells through Cooperative NOD-like Receptor and Toll-like Receptor Signaling

2014 ◽  
Vol 15 (6) ◽  
pp. 779-791 ◽  
Author(s):  
Aaron Burberry ◽  
Melody Y. Zeng ◽  
Lei Ding ◽  
Ian Wicks ◽  
Naohiro Inohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
Hematopoietic Stem

Slug Plays an Essential Role in the Radioprotection of Hematopoietic Progenitors In Vivo by Antagonizing p53-Mediated Apoptotic Pathways.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 31-31
Author(s):  
Wen-Shu Wu ◽  
Dong Xu ◽  
Stefan Heinrichs ◽  
A. Thomas Look
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Γ Irradiation ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Myeloid Progenitors

Abstract An antiapoptotic role for Slug/Snail in mammals was suggested by studies in C. elegans, where CES-1/Scratch, a member of the Slug/Snail superfamily, was found to control the apoptotic death of NSM sister neurons by acting as a transcriptional repressor of EGL-1, a BH3-only proapoptotic protein. Identification of Slug as the target gene of the E2A-HLF oncoprotein in human pro-B leukemia cells led us to demonstrate its antiapoptotic function in IL-3-dependent murine pro-B cells. In contrast to its aberrant expression in pro-B leukemia cells, endogenous Slug is normally expressed in both LT-HSC and ST-HSC, as well as committed progenitors of the myeloid series, but not in pro-B and pro-T cells, implying its function in myelopoiesis. Using Slug−/− mice produced in our laboratory, we showed that these knockouts are much more radiosensitive than Slug+/− and wild-type mice, and that apoptotic cells increase significantly in the hematopoietic progenitor cells of Slug−/− mice as compared to wild-type mice following γ-irradiation, indicating a radioprotective function in vivo. We showed here that although the development of myeloid progenitors is not impaired under steady-state conditions, their repopulation is incomplete γ-irradiated in in Slug−/− mice. We demonstrate further the radiation-induced death of Slug−/− mice is exclusively a result of bone marrow failure with no apparent contribution from systemic injures to other tissues. By two-way bone marrow transplantation, we provide firm evidence that Slug protects mice from γ-irradiation-induced death in a cell-autonomous manner. Interestingly, regenerative capacity of hematopoietic stem cells (HSC) was retained in irradiated Slug−/− mice, which could be rescued by wild-type bone marrow cells after irradiation, indicating that Slug exerts its radioprotective function in myeloid progenitors rather than HSCs. Furthermore, we establish that Slug radioprotects mice by antagonizing downstream of the p53-mediated apoptotic signaling through inhibition of the p53-resposive proapoptotic gene Puma, leading in turn to inhibition of the mitochondria-dependent apoptotic pathway activated by γ-irradiation in myeloid progenitors. More interestingly, we observed that Slug is inducible by γ-irradiation in a p53-dependent manner. Together, our findings implicate a novel Slug-mediated feedback mechanism by which p53 control programmed cell death in myeloid progenitor cells in vivo in response to γ-irradiation.

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