Zu den Inhalten springen

Innate immunity group

Head: M.Prinz

Our group focuses on the role of the brain specific innate immune system. Important molecules involved in innate immunity are chemokine receptors, Toll-like receptors (TLRs) and cytokines such as interferons. Major player of this system within the brain are brain macrophages (microglia) which serve as the first barrier for invading pathogens. We are currently investigating the mechanisms by which microglia contribute to the induction and resolution of brain damage using mouse models of multiple sclerosis (EAE, cuprizone model) and neurodegeneration, e.g. Alzheimers disease.

Personalia

Prof. Dr. Marco Prinz Principal Investigator +49-761-270-51060
Dr. Lukas Amann Postdoc +49-761-270-63114
Dr. Fabian Hersperger Postdoc, Lab-Manager +49-761-270-63108
Dr. Chintan Mukeshbhai Chhatbar Postdoc +49-761-270-93380
Dr. James Cook Postdoc +49-761-270-63111
Dr. Anaelle Dumas Postdoc +49-761-270-63112
Dr. Tatsuyuki Matsudaira Postdoc +49-761-270-63111
Dr. Elena Guffart Postdoc +49-761-270-63091
Dr. Michael Schulz Postdoc +49-761-270-63137
Dr. Han Gao Postdoc +49-761-270-63136
Dr. Gianni Monaco Bioinformatician +49-761-270-93380
Maximilian Fliegauf Phd Student +49-761-270-63113
Adrià Dalmau Gasull Phd Student +49-761-270-63112
Nishita S. Ghariwala Master Student +49-761-270-63112
Shin-ichiro Hiraga Guest Researcher +49-761-270-63136
Saskia Wundt Technician +49-761-270-63114
Maria Oberle Technician +49-761-270-50740

Research Topics

1. Microglia origin, fate and function

Microglia are tissue-resident macrophages in the central nervous system (CNS). They belong to a group of mononuclear phagocytes that comprises peripheral tissue macrophages, CNS-associated macrophages, dendritic cells and monocyte-derived cells (Prinz & Priller 2014). As such they are critical effectors and regulators of changes in CNS homeostasis during development and in health and disease (Prinz et al. 2011). All mononuclear cells originate from hematopoietic stem cells (HSCs) and develop along distinct differentiation pathways in response to endogenous and environmental cues. It was assumed that bone marrow-derived monocytes, a subgroup of leukocytes, circulate in the blood and enter the tissues (where they differentiate into tissue-resident macrophages) in non-pathological conditions and during inflammation. However, this view has been markedly changed in recent years as a result of the discovery of new subtypes of mononuclear phagocytes and their distinct roles in CNS disorders. In the past our lab could identify the peripheral bone marrow-derived precursor that gives rise to microglia during diseases (Mildner et al. 2007). Recently, our lab was able to identify the microglia precursor in the yolk sac and could further decipher the transcriptional program that is required for the development of erythromyeloid precursors to mature microglia during development (Kierdorf et al. 2013). Furthermore, our lab established the first inducible microglia-specific Cre mouse for gene targeting in those cells (Goldmann, Wieghofer et al. 20013). In sum, our research revealed a pivotal role of microglia for the CNS during health and disease.

Figure: IMARIS-based three-dimensional reconstruction of a microglia cell (from Goldmann, Wieghofer et al. 2013).

References:

Goldmann T, Wieghofer P, Müller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszweski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M:. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nature Neuroscience, 2013, 16(11):1618-26. Including cover image (.pdf file)

Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C, Müller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M: Microglia emerge from erythromyeloid precursors via Pu.1 and IRF-8 dependent pathways. Nature Neuroscience, 2013, 16(3):273-80. Including highlight in news & views (.pdf file)

Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwälder M, Brück W, Priller J, Prinz M: Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neuroscience, 2007, 10(12):1544-53. Including highlight in news & views (.pdf file)

Prinz M, Priller J, Sisodia SS, Ransohoff RM: Heterogeneity of central nervous system myeloid cells and their roles in neurodegeneration. Nature Neuroscience, 2011, 13(10):1227-35 (.pdf file)

Prinz M, Priller J: Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nature Review Neuroscience, 2014, 15(5):300-12 (.pdf file)

Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Sagar, Datta M, Drougard A, Stempfl T, Ardura-Fabregat A, Staszewski O, Margineanu A, Sporbert A, Steinmetz LM, Pospisilik JA, Jung S, Priller J, Grün D, Ronneberger O, Prinz M: A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nature Neuroscience, 2017, 20(6):793-803 (,pdf file)

2. Interferons and the brain

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. We demonstrated that mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease (EAE) accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune responses (Prinz et al. 2008). The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS (Prinz et al. 2008). The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. We could recently identify a novel function for RLHs as negative regulators of TH1/TH17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis (Dann et al. 2012).

References:

Dann A, Poeck H, Croxford AL, Gaupp S, Kierdorf K, Knust M, Pfeifer D, Maihoefer C, Endres S, Kalinke U, Meuth SG, Wiendl H, Knobeloch KP, Akira S, Waisman A, Hartmann G, Prinz M: Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation of the CNS. Nature Neuroscience, 2012, 15(1):98-106. (.pdf file)              

Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, Lang R, Martin R, Gold R, Becher B, Brück W, Kalinke U: Distinct and non-redundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity, 2008, 28(5):675-786. Including highlight in news & views and cover image (.pdf file)

Blank T, Detje CN, Spieß A, Hagemeyer N, Brendecke SM, Wolfart J, Staszewski O, Zöller T, Papageorgiou I, Schneider J, Paricio-Montesinos R, Eisel UL, Manahan-Vaughan D, Jansen S, Lienenklaus S, Lu B, Imai Y, Müller M, Goelz SE, Baker DP, Schwaninger M, Kann O, Heikenwalder M, Kalinke U, Prinz M: Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity, 2016, 44:901-12 (,pdf file)