red pulp macrophages; development; GM-CSF; PPAR-gamma; alveolar macrophages
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
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Nobs Samuel Philip, Kopf Manfred (2018), PPAR-γ in innate and adaptive lung immunity, in Journal of Leukocyte Biology
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
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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
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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.