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Cells
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The Impact of Immune Activation on Hematopoiesis
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The Impact of Immune Activation on Hematopoiesis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 56596

Special Issue Editors

Dr. Katherine C. MacNamara

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Guest Editor
Department of Immunology and Microbial Diseases, Albany Medical College, Albany, NY, USA
Interests: hematopoiesis; infectious disease; inflammation; interferons and cytokines; emergency myelopoiesis; macrophages; inflammation-resolution; bone marrow failure
Dr. Martijn A. Nolte

E-Mail Website
Guest Editor
Molecular Cell Biology Lab, Department of Molecular & Cellular Hemostasis, Sanquin, Amsterdam, The Netherlands
Interests: hematopoiesis; stress erythropoiesis; anemia; immune activation; anti-viral immunity; effector T cell formation; T cell migration; costimulatory molecules; inflammatory cytokines

Special Issue Information

Dear Colleagues,

Hematopoiesis is the dynamic and adaptable process of blood cell generation in the bone marrow,  which can be modulated by a variety of conditions, including infection, trauma, and disease. In fact, the very immune cells generated by hematopoiesis can, in turn, impact blood cell generation through a variety of effector mechanisms, including production of cytokines and interferons. How immune activation impacts hematopoiesis is a topic of increasing interest in the context of infection, injury, disease, and aging, as changes to hematopoietic output may directly contribute to host protection and/or pathogenesis. Immune activating conditions can induce the generation of blood cells that differ in quantity and quality, and this may have important consequences on physiology and health. Delineating the mechanisms driving such tailored hematopoietic responses may reveal pathways that can be targeted to improve blood cell generation or suppress production of cells that contribute to pathological responses.

The aim of this special issue is to provide a combination of reviews and research papers, in which the impact of distinct types of immune activation on the hematopoietic process is addressed. The following is a non-exhaustive list of (patho)physiologically relevant conditions that would fit this topic:

  • Infection (viral, bacterial, fungal)
  • Sterile inflammation
  • Autoimmune diseases
  • Autoinflammatory diseases
  • Graft vs host disease
  • Anti-tumor responses
  • TIL & CAR therapy
  • Microbial dysbiosis
  • Ageing
  • Vaccination
We hope that the topics presented by expert laboratories in this field will fuel novel research endeavors to improve our understanding on how bone marrow output can be affected, and thereby lead to novel treatment modalities for patients suffering from anemia or bone marrow diseases.

Dr. Katherine C. MacNamara
Dr. Martijn A. Nolte
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hematopoiesis
  • Immune activation
  • Inflammation
  • Demand-adapted hematopoiesis
  • Hematopoietic stem and progenitor cells
  • Bone marrow

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 464 KiB  
Editorial
Code Red in the Supply Center: The Impact of Immune Activation on Hematopoiesis
by Katherine C. MacNamara and Martijn A. Nolte
Cells 2022, 11(9), 1586; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091586 - 09 May 2022
Viewed by 1384
Abstract
This Special Issue entitled “The Impact of Immune Activation on Hematopoiesis” aims to bring together review and primary articles focused on distinct types of immune activation that impact hematopoiesis [...] Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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Research

Jump to: Editorial, Review

16 pages, 2561 KiB  
Article
PU.1 Expression Defines Distinct Functional Activities in the Phenotypic HSC Compartment of a Murine Inflammatory Stress Model
by James S. Chavez, Jennifer L. Rabe, Giovanny Hernandez, Taylor S. Mills, Katia E. Niño, Pavel Davizon-Castillo and Eric M. Pietras
Cells 2022, 11(4), 680; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040680 - 15 Feb 2022
Cited by 6 | Viewed by 2395
Abstract
The transcription factor PU.1 is a critical regulator of lineage fate in blood-forming hematopoietic stem cells (HSC). In response to pro-inflammatory signals, such as the cytokine IL-1β, PU.1 expression is increased in HSC and is associated with myeloid lineage expansion. To address potential [...] Read more.
The transcription factor PU.1 is a critical regulator of lineage fate in blood-forming hematopoietic stem cells (HSC). In response to pro-inflammatory signals, such as the cytokine IL-1β, PU.1 expression is increased in HSC and is associated with myeloid lineage expansion. To address potential functional heterogeneities arising in the phenotypic HSC compartment due to changes in PU.1 expression, here, we fractionated phenotypic HSC in mice using the SLAM surface marker code in conjunction with PU.1 expression levels, using the PU.1-EYFP reporter mouse strain. While PU.1lo SLAM cells contain extensive long-term repopulating activity and a molecular signature corresponding to HSC activity at steady state, following IL-1β treatment, HSCLT induce PU.1 expression and are replaced in the PU.1lo SLAM fraction by CD41+ HSC-like megakaryocytic progenitors (SL-MkP) with limited long-term engraftment capacity. On the other hand, the PU.1hi SLAM fraction exhibits extensive myeloid lineage priming and clonogenic activity and expands rapidly in response to IL-1β. Furthermore, we show that EPCR expression, but not CD150 expression, can distinguish HSCLT and SL-MkP under inflammatory conditions. Altogether, our data provide insights into the dynamic regulation of PU.1 and identify how PU.1 levels are linked to HSC fate in steady state and inflammatory stress conditions. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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Graphical abstract

18 pages, 4274 KiB  
Article
Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen
by Marieke Goedhart, Edith Slot, Maria F. Pascutti, Sulima Geerman, Timo Rademakers, Benjamin Nota, Stephan Huveneers, Jaap D. van Buul, Katherine C. MacNamara, Carlijn Voermans and Martijn A. Nolte
Cells 2022, 11(1), 55; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010055 - 24 Dec 2021
Cited by 3 | Viewed by 2600
Abstract
Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can [...] Read more.
Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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9 pages, 5497 KiB  
Article
Broad-Spectrum Antibiotics Deplete Bone Marrow Regulatory T Cells
by Hyojeong Han, Hannah Yan and Katherine Y. King
Cells 2021, 10(2), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020277 - 30 Jan 2021
Cited by 15 | Viewed by 3347
Abstract
Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of [...] Read more.
Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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Review

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16 pages, 2487 KiB  
Review
Immune Dysfunction, Cytokine Disruption, and Stromal Changes in Myelodysplastic Syndrome: A Review
by Olivia F. Lynch and Laura M. Calvi
Cells 2022, 11(3), 580; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030580 - 08 Feb 2022
Cited by 8 | Viewed by 3268
Abstract
Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by bone marrow dysfunction and increased risk of transformation to leukemia. MDS represent complex and diverse diseases that evolve from malignant hematopoietic stem cells and involve not only the proliferation of malignant cells but also the [...] Read more.
Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by bone marrow dysfunction and increased risk of transformation to leukemia. MDS represent complex and diverse diseases that evolve from malignant hematopoietic stem cells and involve not only the proliferation of malignant cells but also the dysfunction of normal bone marrow. Specifically, the marrow microenvironment—both hematopoietic and stromal components—is disrupted in MDS. While microenvironmental disruption has been described in human MDS and murine models of the disease, only a few current treatments target the microenvironment, including the immune system. In this review, we will examine current evidence supporting three key interdependent pillars of microenvironmental alteration in MDS—immune dysfunction, cytokine skewing, and stromal changes. Understanding the molecular changes seen in these diseases has been, and will continue to be, foundational to developing effective novel treatments that prevent disease progression and transformation to leukemia. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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20 pages, 2218 KiB  
Review
Early Life Inflammation and the Developing Hematopoietic and Immune Systems: The Cochlea as a Sensitive Indicator of Disruption
by Kelly S. Otsuka, Christopher Nielson, Matthew A. Firpo, Albert H. Park and Anna E. Beaudin
Cells 2021, 10(12), 3596; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123596 - 20 Dec 2021
Cited by 7 | Viewed by 3257
Abstract
Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing [...] Read more.
Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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9 pages, 224 KiB  
Review
Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults
by Jennifer M.-L. Tjon, Saskia M. C. Langemeijer and Constantijn J. M. Halkes
Cells 2021, 10(11), 2905; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112905 - 27 Oct 2021
Cited by 7 | Viewed by 2375
Abstract
Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG [...] Read more.
Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
17 pages, 1702 KiB  
Review
Hematopoietic Dysfunction during Graft-Versus-Host Disease: A Self-Destructive Process?
by Konradin F. Müskens, Caroline A. Lindemans and Mirjam E. Belderbos
Cells 2021, 10(8), 2051; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082051 - 10 Aug 2021
Cited by 7 | Viewed by 5856
Abstract
Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic (stem) cell transplantation (HCT). Clinically, GvHD is associated with severe and long-lasting hematopoietic dysfunction, which may contribute to the high mortality of GvHD after HCT. During GvHD, excessive immune activation damages both hematopoietic [...] Read more.
Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic (stem) cell transplantation (HCT). Clinically, GvHD is associated with severe and long-lasting hematopoietic dysfunction, which may contribute to the high mortality of GvHD after HCT. During GvHD, excessive immune activation damages both hematopoietic stem and progenitor cells and their surrounding bone marrow niche, leading to a reduction in cell number and functionality of both compartments. Hematopoietic dysfunction can be further aggravated by the occurrence—and treatment—of HCT-associated complications. These include immune suppressive therapy, coinciding infections and their treatment, and changes in the microbiome. In this review, we provide a structured overview of GvHD-mediated hematopoietic dysfunction, including the targets in the bone marrow, the mechanisms of action and the effect of GvHD-related complications and their treatment. This information may aid in the identification of treatment options to improve hematopoietic function in patients, during and after GvHD. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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13 pages, 1032 KiB  
Review
Inflammation and Aging of Hematopoietic Stem Cells in Their Niche
by Daozheng Yang and Gerald de Haan
Cells 2021, 10(8), 1849; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081849 - 21 Jul 2021
Cited by 18 | Viewed by 5264
Abstract
Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight [...] Read more.
Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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15 pages, 1386 KiB  
Review
Inflammation, Aging and Hematopoiesis: A Complex Relationship
by Pavlos Bousounis, Veronica Bergo and Eirini Trompouki
Cells 2021, 10(6), 1386; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061386 - 04 Jun 2021
Cited by 20 | Viewed by 6219
Abstract
All vertebrate blood cells descend from multipotent hematopoietic stem cells (HSCs), whose activity and differentiation depend on a complex and incompletely understood relationship with inflammatory signals. Although homeostatic levels of inflammatory signaling play an intricate role in HSC maintenance, activation, proliferation, and differentiation, [...] Read more.
All vertebrate blood cells descend from multipotent hematopoietic stem cells (HSCs), whose activity and differentiation depend on a complex and incompletely understood relationship with inflammatory signals. Although homeostatic levels of inflammatory signaling play an intricate role in HSC maintenance, activation, proliferation, and differentiation, acute or chronic exposure to inflammation can have deleterious effects on HSC function and self-renewal capacity, and bias their differentiation program. Increased levels of inflammatory signaling are observed during aging, affecting HSCs either directly or indirectly via the bone marrow niche and contributing to their loss of self-renewal capacity, diminished overall functionality, and myeloid differentiation skewing. These changes can have significant pathological consequences. Here, we provide an overview of the current literature on the complex interplay between HSCs and inflammatory signaling, and how this relationship contributes to age-related phenotypes. Understanding the mechanisms and outcomes of this interaction during different life stages will have significant implications in the modulation and restoration of the hematopoietic system in human disease, recovery from cancer and chemotherapeutic treatments, stem cell transplantation, and aging. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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17 pages, 644 KiB  
Review
Toll-Like Receptor Signaling in the Establishment and Function of the Immune System
by Jahnavi Aluri, Megan A. Cooper and Laura G. Schuettpelz
Cells 2021, 10(6), 1374; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061374 - 02 Jun 2021
Cited by 51 | Viewed by 8485
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and [...] Read more.
Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity. Full article
(This article belongs to the Special Issue The Impact of Immune Activation on Hematopoiesis)
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