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IFNβ as regulator of CD14/TLR4-mediated microglial responses to CNS infection and damage

dc.contributor.advisorBrück, Wolfgang Prof. Dr.
dc.contributor.authorDöring, Christin
dc.titleIFNβ as regulator of CD14/TLR4-mediated microglial responses to CNS infection and damagede
dc.contributor.refereeBrück, Wolfgang Prof. Dr.
dc.description.abstractengMicroglia 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
dc.contributor.coRefereeWienands, Jürgen Prof. Dr.
dc.contributor.thirdRefereeEhrenreich, Hannelore Prof. Dr. Dr.
dc.subject.engToll-like receptorsde
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullNeuroanatomie, Neurophysiologie, Neuropathologie (PPN619876255)de
dc.subject.gokfullImmunologie {Medizin} (PPN619875453)de

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