bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–02–20
fiveteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Hematopoiesis, Inflammation and Aging-The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals.
  2. Ageing Research Reviews Special Issue Dedicated to Women in Aging Research.
  3. The Role of Nutrients in Maintaining Hematopoietic Stem Cells and Healthy Hematopoiesis for Life.
  4. IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.
  5. Inflammation Regulates Haematopoietic Stem Cells and Their Niche.
  6. Clonal hematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study).
  7. Aging alters the metabolic flux signature of the ER-unfolded protein response in vivo in mice.
  8. Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity.
  9. The hematopoietic saga of clonality in sickle cell disease.
  10. Inflammasome Activation in Myeloid Malignancies-Friend or Foe?
  11. Ketones to the rescue of the starving fly.
  12. Telomere dysfunction in ageing and age-related diseases.
  13. Omicron-targeted vaccines do no better than original jabs in early tests.
  14. Daily briefing: Why COVID-19 reinfections are surging.
  15. COVID-19 boosts risk of heart disease 1 year later.
  1. J Clin Med. 2022 Jan 28. pii: 706. [Epub ahead of print]11(3):
    Hematopoiesis, Inflammation and Aging-The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals.
    Øystein Bruserud, Anh Khoi Vo, Håkon Rekvam.
      Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.
    Keywords:  C-reactive protein; aging; anemia; hematopoiesis; inflammation; survival
    DOI:  https://doi.org/10.3390/jcm11030706
  2. Ageing Res Rev. 2022 Feb 11. pii: S1568-1637(22)00031-9. [Epub ahead of print] 101589
    Ageing Research Reviews Special Issue Dedicated to Women in Aging Research.
    Nicole Noren Hooten, Robert M Brosh.
      
    DOI:  https://doi.org/10.1016/j.arr.2022.101589
  3. Int J Mol Sci. 2022 Jan 29. pii: 1574. [Epub ahead of print]23(3):
    The Role of Nutrients in Maintaining Hematopoietic Stem Cells and Healthy Hematopoiesis for Life.
    Yuko Tadokoro, Atsushi Hirao.
      Nutrients are converted by the body to smaller molecules, which are utilized for both anabolic and catabolic metabolic reactions. Cooperative regulation of these processes is critical for life-sustaining activities. In this review, we focus on how the regulation of nutrient-driven metabolism maintains healthy hematopoietic stem cells (HSCs). For this purpose, we have examined the metabolic regulation of HSCs from two perspectives: (1) the control of intracellular metabolism by the balance of anabolic and catabolic reactions; and (2) the control of organismal metabolic status and hematopoiesis by dietary intake of nutrients. Critical roles of catabolic regulators in stem cell homeostasis are conserved in several types of tissues, including hematopoiesis. These catabolic signals are also major regulators of organismal lifespan in multiple species. In parallel, changes to nutrients via alterations to dietary intake affect not only an organism's metabolic state but also the behavior of its stem cells. While the molecular mechanisms involved in these two aspects of nutrient function may not necessarily overlap, a deeper understanding of these phenomena will point to new avenues of medical research and may furnish new agents for improving human health care.
    Keywords:  anabolism; catabolism; dietary intervention; hematopoietic stem cell; nutrient
    DOI:  https://doi.org/10.3390/ijms23031574
  4. Leukemia. 2022 Feb 12.
    IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.
    Boaz Nachmias, Dilshad H Khan, Veronique Voisin, Arvind S Mer, Geethu Emily Thomas, Nadav Segev, Jonathan St-Germain, Rose Hurren, Marcela Gronda, Aaron Botham, Xiaoming Wang, Neil Maclean, Ayesh K Seneviratne, Nathan Duong, Changjiang Xu, Andrea Arruda, Elias Orouji, Arash Algouneh, Razqallah Hakem, Liran Shlush, Mark D Minden, Brian Raught, Gary D Bader, Aaron D Schimmer.
      AML cells are arranged in a hierarchy with stem/progenitor cells giving rise to more differentiated bulk cells. Despite the importance of stem/progenitors in the pathogenesis of AML, the determinants of the AML stem/progenitor state are not fully understood. Through a comparison of genes that are significant for growth and viability of AML cells by way of a CRISPR screen, with genes that are differentially expressed in leukemia stem cells (LSC), we identified importin 11 (IPO11) as a novel target in AML. Importin 11 (IPO11) is a member of the importin β family of proteins that mediate transport of proteins across the nuclear membrane. In AML, knockdown of IPO11 decreased growth, reduced engraftment potential of LSC, and induced differentiation. Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.
    DOI:  https://doi.org/10.1038/s41375-022-01513-4
  5. Int J Mol Sci. 2022 Jan 20. pii: 1125. [Epub ahead of print]23(3):
    Inflammation Regulates Haematopoietic Stem Cells and Their Niche.
    Nicole Pui-Yu Ho, Hitoshi Takizawa.
      Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs.
    Keywords:  bone marrow niche; haematopoietic stem cells; inflammation
    DOI:  https://doi.org/10.3390/ijms23031125
  6. Rheumatology (Oxford). 2022 Feb 17. pii: keac108. [Epub ahead of print]
    Clonal hematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study).
    Clémence David, Nicolas Duployez, Philippine Eloy, Drifa Belhadi, Julie Chezel, Véronique Le Guern, Cédric Laouénan, Laurène Fenwarth, Diane Rouzaud, Alexis Mathian, Sébastien de Almeida Chaves, Pierre Duhaut, Olivier Fain, Lionel Galicier, Pascale Ghillani-Dalbin, Jean Emmanuel Kahn, Nathalie Morel, Laurent Perard, Micheline Pha, Francoise Sarrot-Reynauld, Olivier Aumaitre, François Chasset, Nicolas Limal, Helene Desmurs-Clavel, Felix Ackermann, Zahir Amoura, Thomas Papo, Claude Preudhomme, Nathalie Costedoat-Chalumeau, Karim Sacre.
       OBJECTIVE: The detection of somatic mutations in genes of myeloid cells in asymptomatic patients - defining clonal hematopoiesis of indeterminate potential (CHIP) - predisposes to cardiovascular events (CVE) in the general population. We aimed to determine whether CHIP was associated with CVE in SLE patients.
    METHODS: The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicenter trial PLUS study conducted from June 2007 through August 2010 at 37 centers in France involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal hematopoiesis was performed on genomic DNA collected at PLUS inclusion. The CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of hematological malignancy. The primary outcome was the incident CVE in SLE.
    RESULTS: Screening for CHIP was performed in 438 SLE patients (38 [29-47] years, 91·8% female). Overall, 63 somatic mutations were identified in 47 patients defining a CHIP prevalence of 10·7% in SLE. Most SLE patients (78·7%) carried a single mutation. Most variants (62·5%) were located in the DNMT3A gene. CHIP was associated with age, age at SLE diagnosis and a lower frequency of antiphospholipid antibodies. CHIP occurred more than 20-years earlier (p < 0·00001) in SLE than in controls. The detection of CHIP at inclusion was not associated with the occurrence of CVE during follow up (HR = 0·42 (0·06 - 3·21), p = 0·406).
    CONCLUSION: The prevalence of CHIP is high in SLE with respect to age but was not associated with incident CVE.
    CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.
    Keywords:  cardiovascular events; clonal hematopoiesis of indeterminate potential; lupus
    DOI:  https://doi.org/10.1093/rheumatology/keac108
  7. Aging Cell. 2022 Feb 16. e13558
    Aging alters the metabolic flux signature of the ER-unfolded protein response in vivo in mice.
    Catherine P Ward, Lucy Peng, Samuel Yuen, John Halstead, Hector Palacios, Edna Nyangau, Hussein Mohammed, Naveed Ziari, Mohamad Dandan, Ashley E Frakes, Holly K Gildea, Andrew Dillin, Marc K Hellerstein.
      Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER ) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a flux "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress with tunicamycin and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared with young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, a significant reduction was seen only in the triglyceride fraction. These data indicate that aged mice have an exaggerated metabolic flux response to ER stress, which may indicate that aging renders the UPRER less effective in resolving proteotoxic stress.
    Keywords:  aging; de novo lipogenesis; endoplasmic reticulum; proteome dynamics; proteomics; unfolded protein response
    DOI:  https://doi.org/10.1111/acel.13558
  8. Front Immunol. 2022 ;13 827250
    Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity.
    Marco De Zuani, Jan Frič.
      Recent evidence shows that innate immune cells, in addition to B and T cells, can retain immunological memory of their encounters and afford long-term resistance against infections in a process known as 'trained immunity'. However, the duration of the unspecific protection observed in vivo is poorly compatible with the average lifespan of innate immune cells, suggesting the involvement of long-lived cells. Accordingly, recent studies demonstrate that hematopoietic stem and progenitor cells (HSPCs) lay at the foundation of trained immunity, retaining immunological memory of infections and giving rise to a "trained" myeloid progeny for a long time. In this review, we discuss the research demonstrating the involvement of HSPCs in the onset of long-lasting trained immunity. We highlight the roles of specific cytokines and Toll-like receptor ligands in influencing HSPC memory phenotypes and the molecular mechanisms underlying trained immunity HSPCs. Finally, we discuss the potential benefits and drawbacks of the long-lasting trained immune responses, and describe the challenges that the field is facing.
    Keywords:  HSPCs; hematopoietic stem cells; innate immunity; myeloid cells; progenitor cells; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2022.827250
  9. J Clin Invest. 2022 Mar 01. pii: e158251. [Epub ahead of print]132(5):
    The hematopoietic saga of clonality in sickle cell disease.
    Aaron J Stonestrom, Ross L Levine.
      Sickle cell disease (SCD) is associated with an increased risk of vascular-occlusive events and of leukemia. Clonal hematopoiesis (CH) may increase both risks. In turn, physiologic abnormalities in SCD may modify the incidence and/or distribution of genetic alterations in CH. In a recent issue of the JCI, Liggett et al. found no difference in CH rate between individuals with versus without SCD. Here we contextualize this report and discuss the complex interplay between CH and SCD with particular attention to consequences for emerging gene therapies. We further consider the limitations in our current understanding of these topics that must be addressed in order to optimize therapeutic strategies for SCD.
    DOI:  https://doi.org/10.1172/JCI158251
  10. Front Cell Dev Biol. 2021 ;9 825611
    Inflammasome Activation in Myeloid Malignancies-Friend or Foe?
    Nicola Andina, Nicolas Bonadies, Ramanjaneyulu Allam.
      Myeloid malignancies including myelodysplastic syndromes, myeloproliferative neoplasms and acute myeloid leukemia are heterogeneous disorders originating from mutated hematopoietic stem and progenitor cells (HSPCs). Genetically, they are very heterogeneous and characterized by uncontrolled proliferation and/or blockage of differentiation of abnormal HSPCs. Recent studies suggest the involvement of inflammasome activation in disease initiation and clonal progression. Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated processing of interleukin (IL) -1-cytokine members IL-1β and IL-18, as well as initiation of gasdermin D-dependent pyroptosis. Inflammasome activation leads to a pro-inflammatory microenvironment in the bone marrow, which drives proliferation and may induce clonal selection of mutated HSPCs. However, there are also contradictory data showing that inflammasome activation actually counteracts leukemogenesis. Overall, the beneficial or detrimental effect of inflammasome activation seems to be highly dependent on mutational, environmental, and immunological contexts and an improved understanding is fundamental to advance specific therapeutic targeting strategies. This review summarizes current knowledge about this dichotomous effect of inflammasome activation in myeloid malignancies and provides further perspectives on therapeutic targeting.
    Keywords:  NLRP3 inflammasome; acute myeloid leukemia and targeting inflammasomes; chronic myeloid leukemia; myelodysplastic syndromes; myeloid malignancies; myeloproliferative neoplasms
    DOI:  https://doi.org/10.3389/fcell.2021.825611
  11. Nat Metab. 2022 Feb 17.
    Ketones to the rescue of the starving fly.
    Kenneth A Wilson, Sudipta Bar, Pankaj Kapahi.
      
    DOI:  https://doi.org/10.1038/s42255-022-00527-7
  12. Nat Cell Biol. 2022 Feb;24(2): 135-147
    Telomere dysfunction in ageing and age-related diseases.
    Francesca Rossiello, Diana Jurk, João F Passos, Fabrizio d'Adda di Fagagna.
      Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.
    DOI:  https://doi.org/10.1038/s41556-022-00842-x
  13. Nature. 2022 Feb 14.
    Omicron-targeted vaccines do no better than original jabs in early tests.
    Emily Waltz.
      
    Keywords:  Immunology; Medical research; Public health; SARS-CoV-2; Vaccines; Virology
    DOI:  https://doi.org/10.1038/d41586-022-00003-y
  14. Nature. 2022 Feb 17.
    Daily briefing: Why COVID-19 reinfections are surging.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-022-00500-0
  15. Science. 2022 Feb 18. 375(6582): 706-707
    COVID-19 boosts risk of heart disease 1 year later.
    Meredith Wadman.
      Giant study shows even mild cases can take a long-term toll on heart and blood vessels.
    DOI:  https://doi.org/10.1126/science.ada1333
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