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Development of alveolar macrophages and splenic red pulp macrophages

English title Development of alveolar macrophages and splenic red pulp macrophages
Applicant Kopf Manfred
Number 163443
Funding scheme Project funding
Research institution Molekulare Gesundheitswissenschaften Departement Biologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Embryology, Developmental Biology
Start/End 01.10.2015 - 30.09.2018
Approved amount 918'000.00
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Keywords (5)

red pulp macrophages; development; GM-CSF; PPAR-gamma; alveolar macrophages

Lay Summary (German)

Lead
In Lungenbläschen lokalisierte Makrophagen dienen als erste Front zur Abwehr von eingeatmeten Pathogenen, sowie der Funktion der Lunge durch den Abbau von spezifischen Lipoproteinen (englisch: surfactant). In diesem Projekt erforschen wir die das genetische Programm und die molekularen Mechanismen der Entwicklung und Funktion dieser Lungenmakrophagen im Embryo und erwachsenen Mäusen.
Lay summary

Makrophagen sind vielseitige Zellen, die in fast allen Geweben und Organen zu finden sind wie z.B. dem Gehirn (Mikroglia), der Leber (Kupffer Zellen), der Haut (Langerhans Zellen), dem Knochen (Osteoklasten), der Milz (Rote Pulpa Makrophagen) und der Lunge (alveolare Makrophagen). Als Phagozyten sind sie generell verantwortlich für die Entfernung von Mikroorganismen und toten Zellen. Zudem üben sie gewebespezifische Funktionen aus. Wie kürzlich gezeigt, entstehen Gewebemakrophagen schon während der Embryonalentwicklung und erneuern sich in den jeweiligen Geweben während des gesamten Lebens durch Zellteilung.  In den Lungenbläschen liegende Makrophagen dienen der Abwehr und dem Abbau von eingeatmeten Partikeln Lipoproteinen, die in der Lunge produziert werden Wir konnten kürzlich zeigen, dass der vom Lungenepithel produzierte Wachstumsfaktor GM-CSF den Transkriptionsfaktor PPARg in Monozyten Stammzellen aktiviert und dadurch die Entwicklung von Lungenmakrophagen kurz vor und nach der Geburt steuert.

Wir wollen nun weitere Gene identifizieren, die von PPARg kontrolliert werden. Durch gezielte Genmanipulation in fötalen Monozyten in Zellkultur und deren Einpflanzung in die Lunge von neugeborenen Mäusen sollen die molekularen Mechanismen der Entwicklung und Funktion von Lungenmakrophagen enthüllt werden.  Mit dieser Methode soll auch ein Modell in Mäusen entwickelt werden für die Gentherapie von Menschen mit einem defekten GM-CSF Gen, die an einer typischen Lungenverschleimung leiden.  Ausserdem wollen wir das Genprogramm der Entwicklung von fötalen Lebermonozyten in fötale Lungenmonozyten studieren.

Direct link to Lay Summary Last update: 19.10.2015

Lay Summary (English)

Lead
Lung macrophages are essential for the first line of defense against inhaled pathogens and lung function by turnover of surfactant lipids. In this project we study the molecular mechanisms of lung macrophage development and function in the fetus and adults.
Lay summary

Macrophages are highly versatile cells localized in almost every tissue and organ of the body including brain (microglia), liver (Kupffer cells), skin (Langerhans cells), bone (osteoclasts), spleen (red pulp macrophages), and lung (alveolar macrophages).  As professional phagocytes they are generally responsible for clearance of invading microorganisms and apoptotic cells.  In addition, they exert tissue specific functions. It has been recently established that the majority of tissue-resident macrophage subsets originate during fetal hematopoiesis and are thereafter maintained by local self-renewal throughout life. Alveolar macrophages (AM) reside in the alveoli of the lung, where they provide the first line of defense and maintain lung function by removal of surfactant and inhaled particles. We have recently shown that GM-CSF produced by lung epithelial cells  instructs AM development by induction of the transcription factor PPARγ in fetal lung monocyte shortly before and after birth.

With this research grant, we want to  (i) identify PPARγ target genes and establish a novel rapid gene targeting technology in fetal monocyte precursors in vitro and subsequent transfer into the lung of neonates to determine gene function in development and function of AM; (ii) establish an animal model for gene therapy of pulmonary alveolar proteinosis in individuals carrying mutations in the GM-CSF or GM-CSF receptor genes. Moreover, we study the genetic program of fetal liver to fetal lung monocyte development. Our proposal comprises a system approach to understand the molecular mechanism of the development and function of alveolar macrophages including massive RNA sequencing and comparison of various stages of fetal monocyte progenitors and mature cells by computational biology combined with gene targeting to assess gene function in vivo.

Direct link to Lay Summary Last update: 19.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation
Muri Jonathan, Heer Sebastian, Matsushita Mai, Pohlmeier Lea, Tortola Luigi, Fuhrer Tobias, Conrad Marcus, Zamboni Nicola, Kisielow Jan, Kopf Manfred (2018), The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation, in Nature Communications, 9(1), 1851-1851.
PPAR-γ in innate and adaptive lung immunity
Nobs Samuel Philip, Kopf Manfred (2018), PPAR-γ in innate and adaptive lung immunity, in Journal of Leukocyte Biology, 1-5.
PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation
Nobs Samuel Philip, Natali Sara, Pohlmeier Lea, Okreglicka Katarzyna, Schneider Christoph, Kurrer Michael, Sallusto Federica, Kopf Manfred (2017), PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation, in The Journal of Experimental Medicine, 214(10), 3015-3035.
Frontline Science: Coincidental null mutation of Csf2rα in a colony of PI3Kγ −/− mice causes alveolar macrophage deficiency and fatal respiratory viral infection
Schneider Christoph, Nobs Samuel P., Heer Alex K., Hirsch Emilio, Penninger Josef, Siggs Owen M., Kopf Manfred (2017), Frontline Science: Coincidental null mutation of Csf2rα in a colony of PI3Kγ −/− mice causes alveolar macrophage deficiency and fatal respiratory viral infection, in Journal of Leukocyte Biology, 101(2), 367-376.
PI3Kγ Is Critical for Dendritic Cell-Mediated CD8+ T Cell Priming and Viral Clearance during Influenza Virus Infection
Nobs Samuel Philip, Schneider Christoph, Heer Alex Kaspar, Huotari Jatta, Helenius Ari, Kopf Manfred (2016), PI3Kγ Is Critical for Dendritic Cell-Mediated CD8+ T Cell Priming and Viral Clearance during Influenza Virus Infection, in PLOS Pathogens, 12(3), e1005508-e1005508.

Collaboration

Group / person Country
Types of collaboration
Manfred Claassen, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Ken Murphy/Washington University School of Medicine, St Louis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Xueli Guan/School of Medicine in Singapore Singapore (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO | EMBL Symposium: Innate Immunity in Host-Pathogen Interactions Poster Superior Capacity of Fetal Monocytes Compared to Primitive Macrophages in Development of Tissue-Resident Macrophages 24.06.2018 Heidelberg, Germany Fengqi Li; Kopf Manfred;
International Symposium „Frontiers in Skin Immunity Talk given at a conference Overlapping and distinct activties of IL-36 and IL-1 cytokines in inflammatory and infectious diseases 22.06.2018 Heidelberg, Germany Kopf Manfred;
Toll 2018 - Translating innate immunity Talk given at a conference The mechanism of NRF2-mediated inflammasome activation 06.06.2018 Porto, Portugal Kopf Manfred;
Seminar at CNIC- Fundación Centro Nacional de Investigaciones Cardiovasculares Individual talk Precursors of tissue macophages 17.02.2018 Madrid, Spain Kopf Manfred;
2nd Type-2 Immunity Meeting Bern Talk given at a conference Mediators of Allergic Lung Inflammtion 15.12.2017 Bern, Switzerland Kopf Manfred;
Respiratory diseases from acute to chronic : what’s (new) in the air?» Talk given at a conference PPARγ in lung immunity 17.11.2017 Paris, France Kopf Manfred;
5th Annual Meeting of the International Cytokine and Interferon Society 2017 Talk given at a conference IL-1 and IL-36 - brothers in arms 29.10.2017 Kanazawa, Japan Kopf Manfred;
FEBS Advanced Course: 19th International Summer School on Immunology Poster Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a crucial role in the red pulp macrophage development 23.09.2017 Hvar, Croatia Kopf Manfred; Okreglicka Katarzyna;
47th annual meeting of the German Society for Immunology Talk given at a conference Unique regulation of Innate and adapitve lung immunity 12.09.2017 Erlangen, Germany Kopf Manfred;
Development of Tissue- and Pathogen-specific Cellular Innate Immunity Talk given at a conference PPARγ in lung immunity 27.07.2017 Freiburg, Germany Kopf Manfred;
Edinburgh Immunology Group Summer Symposium 2017 Talk given at a conference Distinct regulation of the lung immune system and allergic inflammation by a fat transcription factor 15.06.2017 Edinburgh, Great Britain and Northern Ireland Kopf Manfred;
WIRM Poster Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a crucial role in the red pulp macrophage development 15.03.2017 Davos, Switzerland Kopf Manfred; Okreglicka Katarzyna;
Autoinflammation Breaks Barriers Talk given at a conference Development and function of lung macrophages and dendritic cells 20.11.2016 Münster, Germany Kopf Manfred;
100 Years of Phagocytes: Cell symposia Talk given at a conference Development and function of alveolar macrophages 19.09.2016 Giardini Naxos, Italy Kopf Manfred;
International Symposium of the Center for Animal Disease Model 2016 Talk given at a conference Lipid species in vascular inflammation, Nrf2 activation, and IL-1 release. 15.07.2016 Tokyo, Japan Kopf Manfred;
American Thoracic Society- 2016 International Conference Talk given at a conference Development of alveolar macrophages 13.05.2016 San Francisco, United States of America Kopf Manfred;
Keystone Meeting Myeloid Cells Poster Peroxisome proliferator-activated receptor gamma (PPARγ) is essential for red pulp macrophage development 10.04.2016 Killarney, Ireland Okreglicka Katarzyna; Kopf Manfred;
Infectious Disease Immunology Meets Molecular Microbiology Talk given at a conference Immune cell metabolism and mechanisms of defense 07.04.2016 Erlangen, Germany, Germany Kopf Manfred;
life science postdoc day Talk given at a conference GM-CSF-dependent primary cultures of fetal liver monocytes (Csf2-cFliMo) are a useful system to study Alveolar Macrophages 05.10.2015 Zurich, Switzerland Fengqi Li;


Associated projects

Number Title Start Funding scheme
182829 Identification of PPARg target genes in macrophages and characterization of their functional roles 01.10.2018 Project funding

Abstract

Macrophages comprise a heterogeneous group of evolutionary ancient mononuclear phagocytes that hat are present in most tissues and organs and whose functions are highly specialized to their specific environments. Reports over the past 5 years have established that the majority of tissue-resident macrophage subsets originate during fetal hematopoiesis and are thereafter maintained by local self-renewal with minimal contribution of bone marrow (BM)-derived progenitors. Alveolar macrophages (AM) reside in the alveoli of the lung, where they provide the first line of defense and maintain lung function in homeostasis by contributing to the turnover of surfactant. Fate mapping and cell transfer experiments have suggested that AM develop from a fetal monocyte precursor, which is derived from a distinct yolk sac erythroid-myeloid progenitor that migrates to the liver and lung. We have recently shown that GM-CSF produced by lung epithelial cells shortly before and after birth instructs AM development by induction of the transcription factor PPAR? in the fetal lung monocyte. In contrast, PPAR? is dispensable for development of macrophages in liver, heart, peritoneum, brain, kidney, fat, and intestine suggesting a unique requirement of PPAR? for AM development. However, we now found that PPAR? is also essential for development of splenic red pulp macrophages. In the work packages proposed in this grant application, we aim at•Identification of genes regulated by the CSF2R-PPAR? pathway and investigate their role in development and function of AM.•Determination of a potential role of CSF2R-PPAR? pathway in commitment of the fetal liver monocyte to fetal lung monocyte progenitor•Determination of the role of c-Myb in AM development•Establishment of a method for rapid gene targeting mediated by CRIPR/Cas9 in primary cultures of fetal liver monocytes (cFLiMo) to study development and function of AM in vivo.•Establishment of a model for gene therapy of a primary CSF2Ra immunodeficiency •Determination of the lipidome of alveolar macrophages and its regulation by PPAR?.•Dissection of the role of PPAR? in development of red pulp macrophagesThis proposal comprises a system approach to understand the molecular mechanism of the development of alveolar and spleen red pulp macrophages including massive RNA sequencing of several fetal progenitor cells, computational biology, and lipidomics combined with rapid CRIPR/Cas9 mediated gene targeting to assess gene function in vivo.
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