scholarly journals Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lindsay A Hohsfield ◽  
Allison R Najafi ◽  
Yasamine Ghorbanian ◽  
Neelakshi Soni ◽  
Joshua Crapser ◽  
...  
Keyword(s):  
White Matter ◽  
Subventricular Zone ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Distinct Pattern ◽  
Adult Brain ◽  
The Brain ◽  
Stimulating Factor ◽  
Insight Into ◽  
Dynamic Wave

Microglia, the brain’s resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white-matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

scholarly journals Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

2021 ◽  
Author(s):  
Lindsay A. Hohsfield ◽  
Allison R. Najafi ◽  
Yasamine Ghorbanian ◽  
Neelakshi Soni ◽  
Joshua D. Crapser ◽  
...  
Keyword(s):  
White Matter ◽  
Subventricular Zone ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Distinct Pattern ◽  
Adult Brain ◽  
Cell Dynamics ◽  
Neurogenic Niche ◽  
Functional Profiles ◽  
Dynamic Wave

AbstractMicroglia, the brain’s resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using sustained colony-stimulating factor 1 receptor inhibition, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from an important neurogenic niche, the subventricular zone, and associated white matter areas. These cells exhibit tremendous chemotaxis potential, migrating radially and tangentially in a dynamic wave and filling the brain in a distinct pattern, to fully replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit distinct phenotypic and functional profiles to endogenous microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into myeloid cell dynamics in an empty microglial niche without contributions from bone marrow-derived cells.

scholarly journals Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

2018 ◽  
Vol 39 (10) ◽  
pp. 1906-1918 ◽  
Author(s):  
Kota Kurisu ◽  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Jian Shi ◽  
Atsushi Kanoke ◽  
...  
Keyword(s):  
Cell Activation ◽  
Infarct Volume ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Neurological Outcomes ◽  
Intact Brain ◽  
The Brain

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

scholarly journals Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection

2018 ◽  
Vol 217 (9) ◽  
pp. 1481-1490 ◽  
Author(s):  
Sivakumar Periasamy ◽  
Jonathan A Harton
Keyword(s):  
Interleukin 1 ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Interleukin 10 ◽  
Dual Function ◽  
Interleukin 17 ◽  
Colony Stimulating Factor ◽  
Immature Myeloid Cells ◽  
Severe Pathology ◽  
Stimulating Factor

Abstract Bacterial pneumonia is a common risk factor for acute lung injury and sepsis-mediated death, but the mechanisms underlying the overt inflammation and accompanying pathology are unclear. Infiltration of immature myeloid cells and necrotizing inflammation mediate severe pathology and death during pulmonary infection with Francisella tularensis. However, eliciting mature myeloid cells provides protection. Yet, the host factors responsible for this pathologic immature myeloid cell response are unknown. Here, we report that while the influx of both mature and immature myeloid cells is strictly MyD88 dependent, the interleukin 1 (IL-1) receptor mediates an important dual function via its ligands IL-1α and IL-1β. Although IL-1β favors the appearance of bacteria-clearing mature myeloid cells, IL-1α contributes to lung infiltration by ineffective and pathologic immature myeloid cells. Finally, IL-1α and IL-1β are not the sole factors involved, but myeloid cell responses during acute pneumonia were largely unaffected by lung levels of interleukin 10, interleukin 17, CXCL1, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

Vanishing White Matter Hyperintensities in CADASIL: A Case Report with Insight into Disease Mechanisms

2020 ◽  
Vol 78 (3) ◽  
pp. 907-910
Author(s):  
Eric Jouvent ◽  
Nassira Alili ◽  
Dominique Hervé ◽  
Hugues Chabriat
Keyword(s):  
White Matter ◽  
White Matter Hyperintensities ◽  
Autosomal Dominant ◽  
Brain Area ◽  
Imaging Features ◽  
Water Influx ◽  
Disease Mechanisms ◽  
The Brain ◽  
Vanishing White Matter ◽  
Insight Into

In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

scholarly journals Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

2019 ◽  
Vol 10 ◽  
Author(s):  
Maja Studencka-Turski ◽  
Gonca Çetin ◽  
Heike Junker ◽  
Frédéric Ebstein ◽  
Elke Krüger
Keyword(s):  
Type I Interferon ◽  
Myeloid Cells ◽  
Interferon Response ◽  
Type I ◽  
The Brain ◽  
Insight Into

scholarly journals Role of colony-stimulating factor in myelopoiesis in murine long-term bone marrow cultures

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1211-1217 ◽  
Author(s):  
DA Lipschitz ◽  
KB Udupa ◽  
JM Taylor ◽  
RK Shadduck ◽  
A Waheed
Keyword(s):  
Bone Marrow ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Colony Stimulating Factor ◽  
Other Substances ◽  
Bone Marrow Cultures ◽  
Medium Change ◽  
Stimulating Factor ◽  
Marrow Cultures

Abstract Weekly medium change or midweek feeding of long-term bone marrow cultures (LTMBCs) results in a significant increase in total myeloid cell production. Proliferative myeloid cells peak 48 hours after feeding, and nonproliferative myeloid cells reach maximum levels at 72 hours. This increase in myelopoiesis is invariably preceded by a significant elevation in biologically and immunologically measurable colony-stimulating factor (CSF) in the supernatants of LTBMC. The level peaks 24 hours after medium change, then gradually returns to basal values. The decrease in CSF relates to its consumption by generating myeloid precursors because no fluctuation in the levels occur in cultures without active myelopoiesis. No significant inhibitors or promoters of CSF were detected. When highly purified L cell CSF, CSF in lung-conditioned medium, or CSF concentrated from LTBMC supernatant is added to cultures, an identical increase in myelopoiesis occurs. Anti- CSF antiserum, added to culture at the time of medium change, totally neutralizes supernatant CSF levels but does not affect myelopoiesis. These findings suggest a potential regulatory role for CSF in myelopoiesis in LTBMC. CSF appears to function within the microenvironment through a mechanism involving cell:cell interactions or by causing the production of other substances that stimulate myelopoiesis. Because exogenous CSF stimulates myelopoiesis, it is likely that it too can react either directly or through microenvironmental cells to stimulate primitive myeloid cells to divide.

scholarly journals Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kevin G Burfeind ◽  
Xinxia Zhu ◽  
Mason A Norgard ◽  
Peter R Levasseur ◽  
Christian Huisman ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Purinergic Receptor ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Ductal Adenocarcinoma ◽  
The Central Nervous System ◽  
Velum Interpositum ◽  
The Brain

Weight loss and anorexia are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. Pharmacologic CCR2 blockade and genetic deletion of Ccr2 both resulted in significantly decreased brain-infiltrating myeloid cells as well as attenuated cachexia during PDAC. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished immune cell recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.

Expression of the Evi-1 zinc finger gene in 32Dc13 myeloid cells blocks granulocytic differentiation in response to granulocyte colony-stimulating factor

1992 ◽  
Vol 12 (1) ◽  
pp. 183-189
Author(s):  
K Morishita ◽  
E Parganas ◽  
T Matsugi ◽  
J N Ihle
Keyword(s):  
Zinc Finger ◽  
Nuclear Dna ◽  
Zinc Finger Protein ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Granulocytic Differentiation ◽  
Altered Expression ◽  
Stimulating Factor

Expression of the Evi-1 gene is frequently activated in murine myeloid leukemias by retroviral insertions immediately 5' or 90 kb 5' of the gene. The Evi-1 gene product is a nuclear, DNA-binding zinc finger protein of 145 kDa. On the basis of the properties of the myeloid cell lines in which the Evi-1 gene is activated, it has been hypothesized that its expression blocks normal differentiation. To explore this proposed role, we have constructed a retrovirus vector containing the gene and examined its effects on an interleukin-3-dependent myeloid cell line that differentiates in response to granulocyte colony-stimulating factor (G-CSF). Expression of the Evi-1 gene in these cells did not alter the normal growth factor requirements of the cells. However, expression of the Evi-1 gene blocked the ability of the cells to express myeloperoxidase and to terminally differentiate to granulocytes in response to G-CSF. This effect was not due to altered expression of the G-CSF receptor or to changes in the initial responses of the cells to G-CSF. These results support the hypothesis that the inappropriate expression of the Evi-1 gene in myeloid cells interferes with the ability of the cells to terminally differentiate.

Mechanism of Myeloid-Derived Suppressor Cell Differentiation in Cancer.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-31-SCI-31
Author(s):  
Dmitry Gabrilovich
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
Cell Surface ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Myeloid Progenitors

Abstract Abstract SCI-31 Myeloid-derived suppressor cells (MDSC) represent an intrinsic part of myeloid cell lineage and comprised of myeloid progenitors and precursors of myeloid cells. In healthy host upon generation in bone marrow immature myeloid cells (IMC) quickly differentiate into mature granulocytes, macrophages, or dendritic cells. In a number of pathological conditions (cancer, various infections diseases, sepsis, trauma, bone marrow transplantation, autoimmune abnormalities) increased production of IMC is associated with partial block of their differentiation and most importantly pathological activation of these cells manifests in up-regulation of arginase, inducible nitric oxide synthase (iNOS) and NO production, increased level of reactive oxygen species (ROS). This results in expansion of IMC with immune suppressive activity. Accumulation of MDSC was detected in practically all mouse tumor models and in patients with different types of cancer. In mice, MDSCs are characterized by the co-expression of myeloid lineage differentiation antigen Gr1 and CD11b. In humans, MDSC are currently defined as CD14-CD11b+ cells or more narrowly as cells that express the common myeloid marker CD33 but lack the expression of markers of mature myeloid and lymphoid cells and the MHC class II molecule HLA-DR. Recently, the morphological heterogeneity of these cells in mice was defined more precisely based on the expression of cell-surface markers Ly6G and Ly6C. Granulocytic MDSCs have a CD11b+Ly6G+Ly6Clow phenotype, whereas MDSCs with monocytic morphology are CD11b+Ly6G-Ly6Chigh. These two subpopulations may have different functions. Accumulation of MDSC is caused by different soluble factors. Recent studies have demonstrated that factors implicated in regulating the expansion of MDSCs can be provisionally split into two main groups with partially overlapping activity. The first group includes factors that are produced primarily by tumor cells and promote the expansion of MDSC through myelopoiesis stimulation, which is associated with inhibition of myeloid-cell differentiation. These factors include stem-cell factor (SCF), macrophage colony-stimulating factor (M-CSF), IL-6, granulocyte/macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) and others. Signalling pathways triggered by most of these factors in MDSCs converge on signal transducer and activator of transcription 3 (STAT3). One of the potential targets for STAT3 was recently identified as S100A8/A9 proteins. Accumulation of these proteins in myeloid progenitors prevents their differentiation and results in expansion of MDSC. The second group of factors are produced primarily by activated T cells and tumor stroma and directly activate MDSC. These factors, which include IFN gamma, IL-13, IL-4 and TGFβ, among others, activate several different signaling pathways in MDSCs that involve STAT6, STAT1, and NF-kB. Most studies have shown that the immune-suppressive function of MDSCs requires direct cell–cell contact, which indicates that they operate either through cell-surface receptors and/or through the release of short-lived soluble mediators. Currently, a number of clinical trials explores the possibility of regulating immune responses in cancer by depleting ot inactivating MDSC in cancer patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

2015 ◽  
Vol 212 (11) ◽  
pp. 1811-1818 ◽  
Author(s):  
Stefan Prokop ◽  
Kelly R. Miller ◽  
Natalia Drost ◽  
Susann Handrick ◽  
Vidhu Mathur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Amyloid Plaques ◽  
Full Potential ◽  
Antibody Treatment ◽  
App Processing ◽  
The Brain

Although central nervous system–resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer’s disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell–based therapies for AD.

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