| dc.contributor.advisor | Brück, Wolfgang Prof. Dr. | |
| dc.contributor.author | Döring, Christin | |
| dc.date.accessioned | 2017-02-15T09:41:09Z | |
| dc.date.available | 2018-01-14T23:50:37Z | |
| dc.date.issued | 2017-02-15 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002B-7D4A-6 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-30 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | IFNβ as regulator of CD14/TLR4-mediated microglial responses to CNS infection and damage | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Brück, Wolfgang Prof. Dr. | |
| dc.date.examination | 2017-01-24 | |
| dc.description.abstracteng | Microglia are the innate immune cells of the central nervous system (CNS). They are capable of sensing
infection and damage through various receptors and consequently trigger an appropriate immune
response. This includes the production of several cytokines and chemokines that modulate immune
functions and can lead to the recruitment of peripheral immune cells into the CNS. Among these, the
neutrophil chemoattractant CXCL1 and the monocyte chemoattractant CCL2 are released in response
to activation of Toll-like receptors (TLRs) as sensors of highly conserved structures on foreign as well
as host molecules. Apart from that, microglia have been demonstrated to secrete interferons (IFNs),
which are crucial cytokines for fighting viral and also bacterial infections.
Here we show that the production of type I interferons can be induced by activation of microglial TLRs. In
response to double-stranded RNA associated with viral infections detected by TLR3, microglia are able
to produce IFNα as well as IFNβ. Furthermore, activation of TLR4 by bacterial ligands and damage-related
factors triggers IFNβ release. In contrast to that, bacterial ligands of TLR2 fail to induce any type
I interferon. These differences in interferon production can be attributed to the differential involvement
of the major TLR signaling routes. We demonstrate that the release of IFNβ exclusively depends on
the presence of the TIR-domain-containing adapter-inducing IFNβ (TRIF), which is only recruited upon
activation of TLR3 and TLR4. Within the TLR4 system, TRIF-dependent signaling further requires the
TLR4 co-receptor CD14 and accordingly, we could show that CD14 enables IFNβ production.
Following their release, type I interferons exert a variety of functions. In addition to their role in host
defenses against infections, several immunomodulatory effects have been identified, which can be either
beneficial or detrimental depending on the disease context. Here we show, how IFNβ differentially
regulates microglial responses to CNS infection and damage. We demonstrate that the production of
CXCL1 and CCL2 in response to TLR activation is controlled by an IFNβ-mediated feedback mechanism.
While CCL2 is positively regulated, CXCL1 is under negative control of type I interferon signaling.
This mechanism is individually organized within different TLR systems. In response to TLR4 activation,
both subunits of the interferon-α/β receptor (IFNAR) cooperatively regulate chemokine production. This
effect is mediated by the canonical type I interferon signaling pathway, which includes janus kinases and
the signal transducer and activator of transcription (STAT)1 and STAT2. In contrast to that, only IFNAR1
and IFNAR2 regulate TLR2-induced chemokine production independent of downstream components of
the canonical type I interferon signaling pathway.
These different regulatory mechanisms of chemokine production also translate into in vivo control of
immune cell infiltration during CNS infection. In a model of gram-negative meningitis, we demonstrate
protective effects of IFNAR1 by prevention of excessive neutrophil infiltration into the brain. This correlates
with the IFNβ-mediated negative control of microglial CXCL1 production. In contrast to that,
neutrophil infiltration in models of gram-positive meningitis and the autoimmune disease neuromyelitis
optica is not controlled by type I interferon signaling. This underlines that immunomodulatory effects of
type I interferons are very specific and highlights the importance of understanding their mode of action. | de |
| dc.contributor.coReferee | Wienands, Jürgen Prof. Dr. | |
| dc.contributor.thirdReferee | Ehrenreich, Hannelore Prof. Dr. Dr. | |
| dc.subject.eng | Microglia | de |
| dc.subject.eng | Interferon | de |
| dc.subject.eng | Toll-like receptors | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7D4A-6-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Neuroanatomie, Neurophysiologie, Neuropathologie (PPN619876255) | de |
| dc.subject.gokfull | Immunologie {Medizin} (PPN619875453) | de |
| dc.description.embargoed | 2018-01-14 | |
| dc.identifier.ppn | 880286121 | |