scholarly journals Type I IFNs drive hematopoietic stem and progenitor cell collapse via impaired proliferation and increased RIPK1-dependent cell death during shock-like ehrlichial infection

2018 ◽  
Vol 14 (8) ◽  
pp. e1007234 ◽  
Author(s):  
Julianne N. P. Smith ◽  
Yubin Zhang ◽  
Jing Jing Li ◽  
Amanda McCabe ◽  
Hui Jin Jo ◽  
...  
Keyword(s):  
Cell Death ◽  
Progenitor Cell ◽  
Type I ◽  
Hematopoietic Stem ◽  
Type I Ifns ◽  
Dependent Cell ◽  
Cell Collapse

scholarly journals Type I interferon signaling is required for activation of the inflammasome during Francisella infection

2007 ◽  
Vol 204 (5) ◽  
pp. 987-994 ◽  
Author(s):  
Thomas Henry ◽  
Anna Brotcke ◽  
David S. Weiss ◽  
Lucinda J. Thompson ◽  
Denise M. Monack
Keyword(s):  
Cell Death ◽  
Type I Interferon ◽  
Infection Type ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Type I ◽  
Type I Ifn ◽  
Caspase 1 ◽  
Dependent Cell

Francisella tularensis is a pathogenic bacterium whose virulence is linked to its ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host-protective multimolecular complex called the inflammasome to release the proinflammatory cytokines interleukin (IL)-1β and -18 and trigger caspase-1–dependent cell death. In this study, we show that cytosolic F. tularensis subspecies novicida (F. novicida) induces a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome-mediated cell death, and release of IL-1β and -18. Extensive type I IFN–dependent cell death resulting in macrophage depletion occurs in vivo during F. novicida infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria monocytogenes but not vacuole-localized Salmonella enterica serovar Typhimurium or extracellular adenosine triphosphate. These results show the specific connection between type I IFN signaling and inflammasome activation, which are two sequential events triggered by the recognition of cytosolic bacteria. To our knowledge, this is the first example of the positive regulation of inflammasome activation. This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses.

Human Nucleophosmin (NPM1) Perturbs Myeloid Development in Zebrafish in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 308-308
Author(s):  
Niccolò Bolli ◽  
Elspeth Payne ◽  
Clemens Grabher ◽  
Adam Johnston ◽  
John Kanki ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Developmental Expression ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Cytoplasmic Transport ◽  
Dependent Cell

Abstract The most frequent genetic alterations in adult cases of Acute Myeloid Leukemia (AML) are mutations in the human nucleophosmin (hNPM1) gene. In about 30% of AMLs this nucleolar phosphoprotein is aberrantly localized to the cytoplasm (hNPMc) due to these mutations affecting the protein’s nuclear shuttling. hNPMc AMLs exhibit distinctive clinical and biological features that have led to its WHO classification as a distinct myeloid neoplasm. Despite its prominent association with AML, in vitro and in vivo models of hNPMc transformation in myeloid cells are lacking and its role in this process remains poorly understood. To further our understanding of hNPM function we are using the zebrafish vertebrate model system that is ideally suited for the in vivo analysis of cellular function and development during embryonic hematopoiesis. Importantly, the wide variety of blood cell types and key cellular factors regulating hematopoiesis are highly conserved between mammals and zebrafish. To investigate the in vivo role of hNPMc in hematopoiesis, we injected mRNAs encoding hNPM1wt and the leukemia-associated mutant hNPMc into one-cell stage zebrafish embryos. By fusing GFP to these hNPM proteins, we were able to follow the developmental expression of hNPM1 and its subcellular localization during embryogenesis. Analysis using confocal microscopy showed that NPMc is localized to the cell cytoplasm, while NPM1wt is found in nucleoli, as in human and mouse cells. These studies demonstrate the conservation of the nuclear-cytoplasmic transport functions of the human proteins in the zebrafish and further support its validity as a model to analyze and determine hNPM function. We also observed that hNPMc is expressed at far lower levels than its wild-type counterpart and is almost undetectable at 36hpf while hNPMwt continues to be expressed. Unlike mammals, two endogenous zebrafish NPM1 proteins were identified and named, zNpm1a and zNpm1b. Both zNpm1a and zNpm1b proteins are ubiquitously expressed in the embryo and demonstrated nucleolar localization. Expression of hNPMwt resulted in its colocalization with endogenous zNpm while hNPMc was able to bring about the export of both zebrafish proteins to the cytoplasm through heterotypic interactions. Co-immunoprecipitation experiments confirmed the interaction between human and zebrafish NPM1 proteins and zNpm1a and zNpm1b were both able to bind and co-immunoprecipitate with hNPM1 and hNPMc. These experiments suggest that transient hNPMc expression during zebrafish hematopoiesis may mimic its function in human leukemic blasts and provide clues to its functional role in AML. Comparable protein levels of either hNPMwt or hNPMc were expressed in embryos, confirmed by western blot at 22–24 hpf, and analyzed by whole mount in situ hybridization (WISH) using antisense RNA markers of specific hematopoietic lineages. Expression of hNPMc caused an increase in cMYB expression at 36 hpf, indicating an increase in the hematopoietic stem cell compartment. Furthermore, myeloid precursors (PU.1 at 22 hpf) also showed an increase upon hNPMc expression; however, mature myeloid cell (MPO and L-plastin at 26 hpf) levels were not increased relative to those in control hNPMwt injected embryos. Interestingly, the expression of hNPMc in p53 mutant embryos resulted in elevated levels of both PU.1 and MPO expressing cells, suggesting that hNPMc in zebrafish can activate p53 dependent cell cycle arrest, senescence or cell death in PU.1 cells prior to differentiation. These in vivo studies of hNPMc function during zebrafish hematopoietic differentiation suggest that hNPMc expression may increase the stem cell/ myeloid precursor compartment and can activate a p53 dependent cell death response in myeloid cells. Taking advantage of the zebrafish system in these continuing studies will further address how hNPMc expression may contribute to leukemogenesis.

scholarly journals Roles of Retinoids and Retinoic Acid Receptors in the Regulation of Hematopoietic Stem Cell Self-Renewal and Differentiation

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Louise E. Purton
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Progenitor Cell ◽  
Retinoic Acid Receptors ◽  
Key Factors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Complex Processes ◽  
Major Interest

Multipotent hematopoietic stem cells (HSCs) sustain blood cell production throughout an individual's lifespan through complex processes ultimately leading to fates of self-renewal, differentiation or cell death decisions. A fine balance between these decisions in vivo allows for the size of the HSC pool to be maintained. While many key factors involved in regulating HSC/progenitor cell differentiation and cell death are known, the critical regulators of HSC self-renewal are largely unknown. In recent years, however, a number of studies describing methods of increasing or decreasing the numbers of HSCs in a given population have emerged. Of major interest here are the emerging roles of retinoids in the regulation of HSCs.

IFN-α induces barrier destabilization and apoptosis in renal proximal tubular epithelium

2008 ◽  
Vol 294 (1) ◽  
pp. C153-C160 ◽  
Author(s):  
Judith Lechner ◽  
Nadia Malloth ◽  
Thomas Seppi ◽  
Bea Beer ◽  
Paul Jennings ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Type I ◽  
Nuclear Condensation ◽  
Type I Ifns ◽  
Effector Caspase ◽  
Proximal Tubular ◽  
Infected Cells ◽  
Renal Proximal Tubular ◽  
Induced Apoptosis

Type I IFNs, like IFN-α, are major immune response regulators produced and released by activated macrophages, dendritic cells, and virus-infected cells. Due to their immunomodulatory functions and their ability to induce cell death in tumors and virus-infected cells, they are used therapeutically against cancers, viral infections, and autoimmune diseases. However, little is known about the adverse effects of type I IFNs on nondiseased tissue. This study examined the effects of IFN-α on cell death pathways in renal proximal tubular cells. IFN-α induced apoptosis in LLC-PK1 cells, characterized by the activation of caspase-3, -8, and -9, DNA fragmentation, and nuclear condensation. IFN-α also caused mitochondrial depolarization. Effector caspase activation was dependent on caspase-8 and -9. In addition to apoptosis, IFN-α exposure also decreased renal epithelial barrier function, which preceded apoptotic cell death. Caspase inhibition did not influence permeability regulation while significantly attenuating and delaying cell death. These results indicate that IFN-α causes programmed cell death in nondiseased renal epithelial cells. IFN-α-induced apoptosis is directed by an extrinsic death receptor signaling pathway, amplified by an intrinsic mitochondrial pathway. Caspase-dependent and -independent apoptotic mechanisms are involved. These findings reveal a novel aspect of IFN-α actions with implications for normal renal function in immune reactions and during IFN-α therapy.

RIG-I-Induced Type I IFNs Promote Regeneration of the Intestinal Stem Cell Compartment during Acute Tissue Damage

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3072-3072 ◽  
Author(s):  
Julius C Fischer ◽  
Michael Bscheider ◽  
Gabriel Eisenkolb ◽  
Alexander Wintges ◽  
Caroline A Lindemans ◽  
...  
Keyword(s):  
Stem Cell ◽  
Epithelial Cells ◽  
Tissue Regeneration ◽  
Advisory Board ◽  
Intestinal Stem Cell ◽  
Interferon Α ◽  
Type I ◽  
Hematopoietic Stem ◽  
Epithelial Regeneration ◽  
Type I Ifns

Abstract Introduction: Although the role of Type I IFNs in initiating host defense against pathogens is well established, recent work highlights the regenerative function of this cytokine family. Yet, despite its involvement in tissue repair, the cellular targets and mechanisms of action by which Type I IFNs act during tissue regeneration are poorly understood. Results: Here, we describe a hitherto unrecognized regenerative function for the RIG-I/MAVS/IFN-I pathway through direct effects on epithelial regeneration. Mice deficient in the RIG-I adaptor MAVS were more sensitive to intestinal barrier damage after total body irradiation (TBI) and, like RIG-I deficient mice, developed worse graft-versus-host disease (GVHD) in a preclinical model for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This phenotype was not associated with changes in the intestinal microbiota, but with a defect in epithelial regeneration. Moreover, in contrast to previous reports in steady-state conditions and after viral challenge, we found that interferon-α/β receptor (IFNAR) signaling in non-hematopoietic epithelial cells was crucial for tissue regeneration after acute damage. Importantly, we could demonstrate that this pathway could be therapeutically targeted with RIG-I agonists, which promoted barrier integrity and prevented GVHD. Mechanistically, Type I IFNs (either RIG-I-induced or recombinant) could promote intestinal stem cell (ISC) growth in crypt organoid cultures, suggesting that stimulation of the ISC compartment led to epithelial regeneration. Conclusion: Our findings suggest that activation of RIG-I and IFN-I can promote regeneration of intestinal epithelial cells and thus offers an innovative therapeutic strategy for the management of acute intestinal injury. Disclosures van den Brink: Merck: Honoraria; Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Regeneron: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee.

scholarly journals Ripk-Mediated Necroptosis Induces Inflammation and Bone Marrow Failure in Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1599-1599
Author(s):  
Justine E. Roderick ◽  
Nicole Hermance ◽  
Matija Zelic ◽  
Matthew Simmons ◽  
Apostolos Polykratis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Type I ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Ifn Γ

Abstract TNF-α and IFN-γ overproduction are features associated with human bone marrow failure syndromes such as Fanconi Anemia (FA) and Aplastic Anemia (AA). Cells from these patients are known to be hypersensitive to TNF-α and IFN-γ-induced cell death. The serine threonine kinases RIPK1 and RIPK3 interact to mediate necroptosis induced by TNF-α, type I or II interferons. We demonstrate that a hematopoietic RIPK1 deficiency results in hematopoietic stem and progenitor cell loss and induction of bone marrow failure. The cell death reflects cell-intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. Hematopoietic failure in these mice is accompanied by increases in serum pro-inflammatory cytokines/chemokines and reduced hematopoietic colony formation in the presence of TNF-α, type I or II interferon. We provide genetic evidence that a RIPK3 deficiency rescues the bone marrow failure and significantly reduces serum cytokine and chemokine levels in Vav-iCre Ripk1fl/fl mice. These data reveal that in the hematopoietic lineage RIPK1 prevents inflammation by suppressing RIPK3 activity and raise the possibility that human bone marrow failure patients may benefit from selective RIPK inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug

2019 ◽  
Vol 116 (11) ◽  
pp. 5071-5076 ◽  
Author(s):  
Shuvojit Banerjee ◽  
Elona Gusho ◽  
Christina Gaughan ◽  
Beihua Dong ◽  
Xiaorong Gu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Small Molecule ◽  
Dna Methyltransferase ◽  
Small Molecule Inhibitor ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Molecule Inhibitor ◽  
Dependent Cell

Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression. Here we report that cell death in response to AZA treatment occurs through the 2′,5′-oligoadenylate synthetase (OAS)-RNase L pathway. OASs are IFN-induced enzymes that synthesize the RNase L activator 2-5A in response to dsRNA. Cells deficient in RNase L or OAS1 to 3 are highly resistant to AZA, as are wild-type cells treated with a small-molecule inhibitor of RNase L. A small-molecule inhibitor of c-Jun NH2-terminal kinases (JNKs) also antagonizes RNase L-dependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZA-induced and RNase L-dependent cell death were increased by transfection of 2-5A, by deficiencies in ADAR1 (which edits and destabilizes dsRNA), PDE12 or AKAP7 (which degrade 2-5A), or by ionizing radiation (which induces IFN-dependent signaling). Finally, OAS1 expression correlates with AZA sensitivity in the NCI-60 set of tumor cell lines, suggesting that the level of OAS1 can be a biomarker for predicting AZA sensitivity of tumor cells. These studies may eventually lead to pharmacologic strategies for regulating the antitumor activity and toxicity of AZA and related drugs.

Excess Heparan Sulphate Inhibits CXCL12-Mediated Hematopoietic Cell Migration and Engraftment After Bone Marrow Transplant in Mice with Mucopolysaccharidosis Type I,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4010-4010
Author(s):  
H. Angharad Watson ◽  
Rebecca J Holley ◽  
Kia J Langford-Smith ◽  
Fiona L Wilkinson ◽  
Toin H van Kuppevelt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Migration ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Heparan Sulphate ◽  
Type I ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Haematopoietic Progenitor Cell

Abstract Abstract 4010 The primary axis of migration for transplanted hematopoietic stem and progenitor cells (HSPC) is CXCL12/CXCR4. Heparan sulphate (HS) is required for CXCL12 presentation and receptor binding, but the functional role of HS is poorly defined. The alpha-L-iduronidase knockout mouse (Idua−/−) accumulates HS and dermatan sulphate, recapitulating the neurodegenerative lysosomal storage disease Mucopolysaccharidosis I Hurler (MPSIH). MPSIH is primarily treated with HSPC transplant, but clinical experience suggests a historical engraftment defect in patients. We show significantly reduced HSPC migration in Idua−/− recipients and under limiting engraftment conditions we show a significant haematopoietic engraftment defect in Idua−/− recipients. No significant donor cell effect was observed. Bone marrow but not peripheral blood CXCL12 levels are slightly elevated in Idua−/− mice. CFU frequency in BM is unchanged between genotypes but reduced significantly in peripheral blood of Idua−/− mice. In whole bone marrow, and on mesenchymal stem cells from Idua−/− mice, HS is present in significant excess, particularly in extracellular matrix, and cell surface locations, with significant increases in all sulphation modifications, especially 2-O-sulphation. Finally we show that excess HS, and particularly HS with increased 2-O -sulphation, functionally inhibit haematopoietic progenitor cell migration in vitro. These data provide novel insight into the influence of highly sulphated HS in CXCL12 mediated haematopoietic progenitor cell migration and help to explain why HSCT engraftment has been historically low in MPSIH. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IFNγ-Induced Necroptosis Contributes to Hematopoietic Stem and Progenitor Cell Death and Bone Marrow Failure

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1485-1485
Author(s):  
Joanne O'Donnell ◽  
Justine E. Roderick ◽  
Manolis Pasparakis ◽  
Michelle Kelliher
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Elevated Serum ◽  
Type Ii ◽  
Cell Type ◽  
Receptor Ligands ◽  
Hematopoietic Stem

Abstract RIPK1 has important kinase-dependent and kinase-independent scaffolding functions that prevent or activate necroptosis or apoptosis. Complete RIPK1 deficiency results in cell death and widespread inflammation yet tissue specific RIPK1 deletion can result in apoptosis, necroptosis and/or systemic inflammation, depending on the cell type. We have previously demonstrated that a hematopoietic RIPK1 deficiency results in constitutive activation of RIPK3 and MLKL and induction of necroptosis (Roderick et al, PNAS, 2014). These mice exhibit elevated serum TNFα and IFNγ levels, hematopoietic stem and progenitor cell (HSPC) loss, and ultimately succumb to bone marrow failure (BMF). When mice with a hematopoietic RIPK1 deficiency were placed on a RIPK3 deficient background, plasma pro-inflammatory cytokine and chemokine levels were reduced, HSPC numbers increased and BMF was significantly delayed. These mouse genetic data demonstrate that necroptotic death contributes to BMF in the mouse. To identify the receptor/ligands that trigger necroptosis, we generated mice with a hematopoietic RIPK1-deficiency on the Tnfr1-/-and Tnfr1-/-Tnfr2-/-genetic backgrounds. An absence of TNF signaling failed to prevent necroptosis and consequently, vav-iCre Ripk1f/f Tnfr1-/- Tnfr2-/-mice succumbed to BMF. Because type II interferons can also induce necroptosis, we generated vav-iCre Ripk1f/f Ifngr1-/- mice. These mice appear phenotypically normal demonstrating that an absence of IFNγ signaling prevents HSPC necroptosis and BMF.Collectively, these data may implicate IFNγ-mediated, RIPK3-dependent necroptosis in human BMF syndromes and raise the intriguing possibility that the progressive HSPC elimination observed in these patients reflects in part, IFNγ-induced necroptotic death. Disclosures No relevant conflicts of interest to declare.

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