• Kontakt
• So finden Sie uns
• Klinikumseinrichtungen
• Presse

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 mechamisms by which microglia contribute to the induction and resolution of brain damage using mouse models of multiple sclerosis (EAE model), toxic de- and remyelination and neurodegerenation, e.g. Alzheimers disease.

Personalia

Research Topics

The role and function of microglia

microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

Figure: Recruitment of donor-derived GFP-labelled (green) monocytes and their differentiation into microglia in the CNS after axotomized facial nucleus (from Mildner et al. NatNeurosci 2008).

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

A. Mildner, M. Djukic, D. Garbe, A. Wellmer, W.A. Kuziel, M. Mack, R. Nau, M. Prinz: Ly-6G+CCR2- myeloid cells rather than Ly-6ChiCCR2+ monocytes are required for the control of bacterial infection in the central nervous system. J Immunol , 2008, 181(4):2713-22.

Interferons and the brain

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. We demonstrated elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. 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.

Reference:
M.Prinz, H.Schmidt, A.Mildner, K.P.Knobeloch, U.-K.Hanisch, C.Detje, I.Gutcher, J.Mages, R.Lang, R.Martin, R.Gold, B.Becher, W.Brück, U.Kalinke: Engagement of IFNAR on myeloid cells determines the course of autoimmunity in the central nervous system. Immunity , 2008, 28(5):675-86.

Brain endogenous NF-kappaB during disease

Activation of transcription factor NF-kappaB in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic. We showed that CNS-restricted ablation of 'upstream' NF-kappaB activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of multiple sclerosis, suggesting that 'canonical' NF-kappaB activation in cells of the CNS has a mainly pathogenic function in autoimmune demyelinating disease. NF-kappaB inhibition prevented the expression of proinflammatory cytokines, chemokines and the adhesion molecule VCAM-1 from CNS-resident cells. Thus, NF-kappaB-dependent gene expression in non-microglial cells of the CNS provides a permissive proinflammatory milieu that is critical for CNS inflammation and tissue damage in autoimmune demyelinating disease.

Reference:
G.van Loo, R.DeLorenzi, H.Schmidt, M.Huth, A.Mildner, M.Schmidt-Supprian, H.Lassmann, M.Prinz, M.Pasparakis: Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nature Immunology , 2006, 7(9):954-961.

• english