Publications by authors named "Melanie Greter"

60 Publications

Monocytes promote UV-induced epidermal carcinogenesis.

Eur J Immunol 2021 Mar 24. Epub 2021 Mar 24.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Mononuclear phagocytes consisting of monocytes, macrophages, and DCs play a complex role in tumor development by either promoting or restricting tumor growth. Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer arising from transformed epidermal keratinocytes. While present at high numbers, the role of tumor-infiltrating and resident myeloid cells in the formation of cSCC is largely unknown. Using transgenic mice and depleting antibodies to eliminate specific myeloid cell types in the skin, we investigated the involvement of mononuclear phagocytes in the development of UV-induced cSCC in K14-HPV8-E6 transgenic mice. Although resident Langerhans cells were enriched in the tumor, their contribution to tumor formation was negligible. Equally, dermal macrophages were dispensable for the development of cSCC. In contrast, mice lacking circulating monocytes were completely resistant to UV-induced cSCC, indicating that monocytes promote tumor development. Collectively, these results demonstrate a critical role for classical monocytes in the initiation of skin cancer.
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http://dx.doi.org/10.1002/eji.202048841DOI Listing
March 2021

Pericytes regulate vascular immune homeostasis in the CNS.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zürich, Zürich University, 8091 Zürich, Switzerland;

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice ( ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in ; mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.
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http://dx.doi.org/10.1073/pnas.2016587118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958247PMC
March 2021

Microglia control small vessel calcification via TREM2.

Sci Adv 2021 Feb 26;7(9). Epub 2021 Feb 26.

Department of Neurosurgery, Clinical Neurocentre, Zurich University Hospital, Zurich University, Zürich, Switzerland.

Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, , to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification.
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http://dx.doi.org/10.1126/sciadv.abc4898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909879PMC
February 2021

The dural sinus hub: more than just a brain drain.

Cell 2021 Feb;184(4):858-860

Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Recent findings of an active neuroimmune exchange at brain border regions have challenged the concept of the immune-privileged central nervous system. The study by Rustenhoven et al. in this issue of Cell shows that dural sinuses serve as a conduit for brain-derived antigens to interact with the immune system, allowing in situ immune surveillance.
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http://dx.doi.org/10.1016/j.cell.2021.01.040DOI Listing
February 2021

Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig University Giessen, 35392 Giessen, Germany;

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64MHCII and CD64MHCII macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.
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http://dx.doi.org/10.1073/pnas.2013686117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817195PMC
January 2021

A Single Metabolite which Modulates Lipid Metabolism Alters Hematopoietic Stem/Progenitor Cell Behavior and Promotes Lymphoid Reconstitution.

Stem Cell Reports 2020 09 27;15(3):566-576. Epub 2020 Aug 27.

Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Electronic address:

Fatty acid β-oxidation (FAO), the breakdown of lipids, is a metabolic pathway used by various stem cells. FAO levels are generally high during quiescence and downregulated with proliferation. The endogenous metabolite malonyl-CoA modulates lipid metabolism as a reversible FAO inhibitor and as a substrate for de novo lipogenesis. Here we assessed whether malonyl-CoA can be exploited to steer the behavior of hematopoietic stem/progenitor cells (HSPCs), quiescent stem cells of clinical relevance. Treatment of mouse HSPCs in vitro with malonyl-CoA increases HSPC numbers compared with nontreated controls and ameliorates blood reconstitution capacity when transplanted in vivo, mainly through enhanced lymphoid reconstitution. Similarly, human HSPC numbers also increase upon malonyl-CoA treatment in vitro. These data corroborate that lipid metabolism can be targeted to direct cell fate and stem cell proliferation. Physiological modulation of metabolic pathways, rather than genetic or pharmacological inhibition, provides unique perspectives for stem cell manipulations in health and disease.
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http://dx.doi.org/10.1016/j.stemcr.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486304PMC
September 2020

Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes.

Cell 2020 06 28;181(7):1626-1642.e20. Epub 2020 May 28.

Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland. Electronic address:

Brain malignancies can either originate from within the CNS (gliomas) or invade from other locations in the body (metastases). A highly immunosuppressive tumor microenvironment (TME) influences brain tumor outgrowth. Whether the TME is predominantly shaped by the CNS micromilieu or by the malignancy itself is unknown, as is the diversity, origin, and function of CNS tumor-associated macrophages (TAMs). Here, we have mapped the leukocyte landscape of brain tumors using high-dimensional single-cell profiling (CyTOF). The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between gliomas and brain metastases (BrM). The glioma TME presented predominantly with tissue-resident, reactive microglia, whereas tissue-invading leukocytes accumulated in BrM. Tissue-invading TAMs showed a distinctive signature trajectory, revealing tumor-driven instruction along with contrasting lymphocyte activation and exhaustion. Defining the specific immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.
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http://dx.doi.org/10.1016/j.cell.2020.04.055DOI Listing
June 2020

Skipping adolescence to become super-inflammatory monocytes.

Nat Immunol 2020 05;21(5):491-492

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41590-020-0652-2DOI Listing
May 2020

Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development.

Cell 2020 Apr 6;181(3):557-573.e18. Epub 2020 Apr 6.

Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Central nervous system (CNS) macrophages comprise microglia and border-associated macrophages (BAMs) residing in the meninges, the choroid plexus, and the perivascular spaces. Most CNS macrophages emerge during development, with the exception of choroid plexus and dural macrophages, which are replaced by monocytes in adulthood. Whether microglia and BAMs share a developmental program or arise from separate lineages remains unknown. Here, we identified two phenotypically, transcriptionally, and locally distinct brain macrophages throughout development, giving rise to either microglia or BAMs. Two macrophage populations were already present in the yolk sac suggesting an early segregation. Fate-mapping models revealed that BAMs mostly derived from early erythro-myeloid progenitors in the yolk sac. The development of microglia was dependent on TGF-β, whereas the genesis of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene signature, and requirement for TGF-β.
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http://dx.doi.org/10.1016/j.cell.2020.03.021DOI Listing
April 2020

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems.

Eur J Immunol 2020 03;50(3):338-341

Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Cre and CreER mouse strains are powerful tools that have proven invaluable for investigating the function of genes and for the fate-mapping of cell populations. The fidelity of these systems however are becoming more and more contested. In this issue of the European Journal of Immunology, Van Hove et al. and Chappell-Maor et al. carefully dissect the cellular specificities of two commonly used CreER mouse strains for the study of CNS macrophages; Cx3cr1 and Sall1 . Both studies elegantly highlight that CreER strains, as well as the "floxed" allele to be targeted, need to be carefully selected and properly characterized in order to ensure reproducible and robust data and interpretations. These studies are a cautionary tale for this technology, but also highlight that we must continuously question and improve our experimental approaches.
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http://dx.doi.org/10.1002/eji.202048546DOI Listing
March 2020

Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.

J Mol Cell Cardiol 2020 02 21;139:24-32. Epub 2020 Jan 21.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, Zurich University Hospital, Zurich, Switzerland. Electronic address:

Aims: Sirtuin 6 (Sirt6) is a NAD-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model.

Methods And Results: Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels.

Conclusions: Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.
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http://dx.doi.org/10.1016/j.yjmcc.2020.01.002DOI Listing
February 2020

Emerging roles of IL-34 in health and disease.

J Exp Med 2020 03;217(3)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Macrophages are part of the innate immune system and are present in every organ of the body. They fulfill critical roles in tissue homeostasis and development and are involved in various pathologies. An essential factor for the development, homeostasis, and function of mononuclear phagocytes is the colony stimulating factor-1 receptor (CSF-1R), which has two known ligands: CSF-1 and interleukin-34 (IL-34). While CSF-1 has been extensively studied, the biology and functions of IL-34 are only now beginning to be uncovered. In this review, we discuss recent advances of IL-34 biology in health and disease with a specific focus on mononuclear phagocytes.
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http://dx.doi.org/10.1084/jem.20190290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062519PMC
March 2020

The CNS Immune Landscape from the Viewpoint of a T Cell.

Trends Neurosci 2019 10 29;42(10):667-679. Epub 2019 Aug 29.

Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address:

Neuro-immune interactions are not only vital for the control of neurotropic pathogens, but also appear to influence brain development and homeostasis. During immune surveillance, T cells can patrol the CNS-associated border regions to sense pathogenic alterations. While access to the CNS parenchyma is restricted in the steady state, various disease processes can initiate parenchymal T cell CNS invasion. However, to breach the glia limitans, T cells must become reactivated within the meningeal spaces. T cells cannot sense native antigens (Ags), but instead recognize small processed peptides bound to MHC molecules and presented on the surface of Ag-presenting cells (APCs). In this review, we focus on (CD4) T cell-CNS interactions that are dependent on Ag recognition. We discuss the potential paths and mechanisms of T cell entry into the CNS, in particular with respect to CNS-resident APCs, which present CNS-derived Ag in the absence of inflammation.
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http://dx.doi.org/10.1016/j.tins.2019.07.008DOI Listing
October 2019

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity.

EMBO J 2019 10 15;38(19):e101233. Epub 2019 Aug 15.

Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.

Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue-specific functions. The latter are induced by signals from the microenvironment and rely on unique tissue-specific molecular programs requiring the combinatorial action of tissue-specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)-a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell-intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome-wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage-inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self-renewal and guardians of their identity.
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http://dx.doi.org/10.15252/embj.2018101233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769426PMC
October 2019

Checking macrophages at the border.

Nat Neurosci 2019 06;22(6):848-850

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41593-019-0411-6DOI Listing
June 2019

Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation.

Sci Immunol 2019 01;4(31)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

The central nervous system (CNS) is under close surveillance by immune cells, which mediate tissue homeostasis, protection, and repair. Conversely, in neuroinflammation, dysregulated leukocyte invasion into the CNS leads to immunopathology and neurological disability. To invade the brain parenchyma, autoimmune encephalitogenic T helper (T) cells must encounter their cognate antigens (Ags) presented via local Ag-presenting cells (APCs). The precise identity of the APC that samples, processes, and presents CNS-derived Ags to autoaggressive T cells is unknown. Here, we used a combination of high-dimensional single-cell mapping and conditional MHC class II ablation across all CNS APCs to systematically interrogate each population for its ability to reactivate encephalitogenic T cells in vivo. We found a population of conventional dendritic cells, but not border-associated macrophages or microglia, to be essential for licensing T cells to initiate neuroinflammation.
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http://dx.doi.org/10.1126/sciimmunol.aau8380DOI Listing
January 2019

Trained Microglia Trigger Memory Loss.

Immunity 2018 05;48(5):849-851

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address:

Innate immune training is a recently described mechanism that allows innate cells to recollect a previous inflammatory episode. In a recent issue of Nature, Wendeln et al. (2018) show that peripheral inflammation can alter long-term microglia function, influencing neuropathology later in life.
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http://dx.doi.org/10.1016/j.immuni.2018.04.033DOI Listing
May 2018

High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease.

Immunity 2018 02 6;48(2):380-395.e6. Epub 2018 Feb 6.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address:

Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease.
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http://dx.doi.org/10.1016/j.immuni.2018.01.011DOI Listing
February 2018

Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner.

Cell 2018 01 21;172(3):500-516.e16. Epub 2017 Dec 21.

Institut de Biologie de l'Ecole normale supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France. Electronic address:

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
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http://dx.doi.org/10.1016/j.cell.2017.11.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786503PMC
January 2018

The Cytokine TGF-β Promotes the Development and Homeostasis of Alveolar Macrophages.

Immunity 2017 11 7;47(5):903-912.e4. Epub 2017 Nov 7.

Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Alveolar macrophages (AMs) derive from fetal liver monocytes, which colonize the lung during embryonic development and give rise to fully mature AMs perinatally. AM differentiation requires granulocyte macrophage colony-stimulating factor (GM-CSF), but whether additional factors are involved in AM regulation is not known. Here we report that AMs, in contrast to most other tissue macrophages, were also dependent on transforming growth factor-β receptor (TGF-βR) signaling. Conditional deletion of TGF-βR in mice at different time points halted the development and differentiation of AMs. In adult mice, TGF-β was also critical for AM homeostasis. The source of TGF-β was AMs themselves, indicative of an autocrine loop that promotes AM self-maintenance. Mechanistically, TGF-βR signaling resulted in upregulation of PPAR-γ, a signature transcription factor essential for the development of AMs. These findings reveal an additional layer of complexity regarding the guidance cues, which govern the genesis, maturation, and survival of AMs.
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http://dx.doi.org/10.1016/j.immuni.2017.10.007DOI Listing
November 2017

EMPhasis on Mutant Microglia: Dysregulation of Brain Sentinels Induces Neurodegeneration.

Cell Stem Cell 2017 11;21(5):566-568

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address:

Reactive microglia are often implicated in the pathology of neurodegenerative disease. In a recent study in Nature, Mass et al. (2017) demonstrate that targeted mutation of Braf in early erythro-myeloid precursors (EMPs) causes histiocytosis-associated late onset neurodegeneration driven by activated microglia.
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http://dx.doi.org/10.1016/j.stem.2017.10.006DOI Listing
November 2017

Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

J Clin Invest 2017 Nov 25;127(11):3937-3953. Epub 2017 Sep 25.

Neuroimmunology Unit.

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2-/- NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.
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http://dx.doi.org/10.1172/JCI92387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663358PMC
November 2017

GM-CSF: From Growth Factor to Central Mediator of Tissue Inflammation.

Immunity 2016 11;45(5):963-973

Institute of Experimental Immunology, University of Zurich Winterthurerstrasse 190, 8057 Zurich, Switzerland.

The granulocyte-macrophage colony-stimulating factor (GM-CSF) was initially classified as a hematopoietic growth factor. However, unlike its close relatives macrophage CSF (M-CSF) and granulocyte CSF (G-CSF), the majority of myeloid cells do not require GM-CSF for steady-state myelopoiesis. Instead, in inflammation, GM-CSF serves as a communication conduit between tissue-invading lymphocytes and myeloid cells. Even though lymphocytes are in all likelihood the instigators of chronic inflammatory disease, GM-CSF-activated phagocytes are well equipped to cause tissue damage. The pivotal role of GM-CSF at the T cell:myeloid cell interface might shift our attention toward studying the function of the myeloid compartment in immunopathology. Targeting specifically the crosstalk between T cells and myeloid cells through GM-CSF holds promise for the development of therapeutics to combat chronic tissue inflammation. Here, we will review some of the major discoveries of the recent past, which indicate that GM-CSF is so much more than its name suggests.
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http://dx.doi.org/10.1016/j.immuni.2016.10.026DOI Listing
November 2016

Sall1 is a transcriptional regulator defining microglia identity and function.

Nat Immunol 2016 Dec 24;17(12):1397-1406. Epub 2016 Oct 24.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Microglia are the resident macrophages of the central nervous system (CNS). Gene expression profiling has identified Sall1, which encodes a transcriptional regulator, as a microglial signature gene. We found that Sall1 was expressed by microglia but not by other members of the mononuclear phagocyte system or by other CNS-resident cells. Using Sall1 for microglia-specific gene targeting, we found that the cytokine receptor CSF1R was involved in the maintenance of adult microglia and that the receptor for the cytokine TGF-β suppressed activation of microglia. We then used the microglia-specific expression of Sall1 to inducibly inactivate the murine Sall1 locus in vivo, which resulted in the conversion of microglia from resting tissue macrophages into inflammatory phagocytes, leading to altered neurogenesis and disturbed tissue homeostasis. Collectively, our results show that transcriptional regulation by Sall1 maintains microglial identity and physiological properties in the CNS and allows microglia-specific manipulation in vivo.
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http://dx.doi.org/10.1038/ni.3585DOI Listing
December 2016

Family ties among CNS macrophages.

Authors:
Melanie Greter

Nat Immunol 2016 06;17(7):742-3

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/ni.3490DOI Listing
June 2016

Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems.

Trends Immunol 2015 Oct;36(10):625-636

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.

Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme before the blood brain barrier is formed. They seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system that is maintained throughout lifespan. The mechanisms through which these embryonic-derived cells contribute to microglia homoeostasis at steady state and upon inflammation are still not entirely clear. Here we review recent studies that provided insight into the contribution of embryonically-derived microglia and of adult 'microglia-like' cells derived from monocytes during inflammation. We examine different microglia depletion models, and discuss the origin of their rapid repopulation after depletion and outline important areas of future research.
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http://dx.doi.org/10.1016/j.it.2015.08.005DOI Listing
October 2015

The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity.

Immunity 2015 Sep 1;43(3):502-14. Epub 2015 Sep 1.

Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland. Electronic address:

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations throughout the myeloid lineages. Experimental autoimmune encephalomyelitis (EAE) progressed normally when either classical dendritic cells (cDCs) or neutrophils lacked GM-CSF responsiveness. The development of tissue-invading monocyte-derived dendritic cells (moDCs) was also unperturbed upon Csf2rb deletion. Instead, deletion of Csf2rb in CCR2(+)Ly6C(hi) monocytes phenocopied the EAE resistance seen in complete Csf2rb-deficient mice. High-dimensional analysis of tissue-infiltrating moDCs revealed that GM-CSF initiates a combination of inflammatory mechanisms. These results indicate that GM-CSF signaling controls a pathogenic expression signature in CCR2(+)Ly6C(hi) monocytes and their progeny, which was essential for tissue damage.
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http://dx.doi.org/10.1016/j.immuni.2015.08.010DOI Listing
September 2015

Microglia Versus Myeloid Cell Nomenclature during Brain Inflammation.

Front Immunol 2015 26;6:249. Epub 2015 May 26.

Institute of Experimental Immunology, University of Zurich , Zurich , Switzerland.

As immune sentinels of the central nervous system (CNS), microglia not only respond rapidly to pathological conditions but also contribute to homeostasis in the healthy brain. In contrast to other populations of the myeloid lineage, adult microglia derive from primitive myeloid precursors that arise in the yolk sac early during embryonic development, after which they self-maintain locally and independently of blood-borne myeloid precursors. Under neuro-inflammatory conditions such as experimental autoimmune encephalomyelitis, circulating monocytes invade the CNS parenchyma where they further differentiate into macrophages or inflammatory dendritic cells. Often it is difficult to delineate resident microglia from infiltrating myeloid cells using currently known markers. Here, we will discuss the current means to reliably distinguish between these populations, and which recent advances have helped to make clear definitions between phenotypically similar, yet functionally diverse myeloid cell types.
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http://dx.doi.org/10.3389/fimmu.2015.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443742PMC
June 2015