Neuroinflammation: Microglia and T Cells Get Ready to Tango

Schetters, Sjoerd; Gómez-Nicola, Diego; García-Vallejo, Juan J.; Kooyk, Yvette van

doi:10.3389/fimmu.2017.01905

Cited by 286 publications

(238 citation statements)

References 110 publications

(139 reference statements)

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“…Furthermore, the severity of viral encephalitis certainly has an impact on specific microglia response. The present findings enhance our understanding of microglia-T cell crosstalk that seems to play a vital role in neuroinflammation, whether through soluble mediators or via contact-dependent interactions (Schetters et al, 2017).…”

Section: Discussionsupporting

confidence: 55%

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Waltl

Käufer

Gerhauser

et al. 2018

Brain, Behavior, and Immunity

113

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In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.

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Section: Discussionsupporting

confidence: 55%

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Waltl

Käufer

Gerhauser

et al. 2018

Brain, Behavior, and Immunity

113

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“…We found that the control neuronal cultures upregulated the phagosome pathway after Aβ-S8C stimulation, namely the genes associated with MHCII. These observations are in line with previous reports where incubation with Aβ led to an accumulation of MHC-II and AD patients also showed up-regulation of MHC-II (Schetters et al, 2017). On the contrary, these genes were not differentially regulated in our AD TREM2 neuronal cultures, but interestingly other genes associated with the phagosome pathway were downregulated.…”

Section: Discussionsupporting

confidence: 93%

IPSC-derived neuronal cultures expressing the Alzheimer’s disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network

Martins

Müller‐Schiffmann

Bohndorf

et al. 2019

Preprint

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Recently, genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer's disease (LOAD). One of them is the rare p.Arg47His (R47H) variant within triggering receptor expressed on myeloid cells 2 (TREM2), which has been shown to increase the risk for developing AD 2-3-fold. Here, we report the generation and characterization of a model of LOAD using lymphoblast-derived iPSCs from patients harbouring the R47H mutation in TREM2 (AD TREM2 iPSCs), as well as from control individuals without dementia (CON iPSCs). iPSCs efficiently differentiate into mature neuronal cultures and comparative global transcriptome analysis identified a distinct gene expression profile in AD TREM2 neuronal cultures. Furthermore, manipulation of the iPSCderived functional neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD TREM2 neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER) which emphasised ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

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“…The mechanisms that enable sustained T-cell activation within the parenchyma are not well understood, in particular, the duration of residence and the requirements for continued activation and survival. While knock out of MHC class II from CNS resident cells reduces infiltration of CD4 + T-cells and ablation of IL-17 signaling in OPCs was shown to specifically weaken EAE disease and immune cell infiltration 6,77,78 , the role of CNS parenchymal MHC class I expression in mediating CD8 + activation remains unknown. Observations from MS pathological studies document CD8 activation in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

Kirby

Jin²,

Cardona

et al. 2018

Preprint

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Oligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10 + oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.

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Neuroinflammation: Microglia and T Cells Get Ready to Tango

Cited by 286 publications

References 110 publications

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

IPSC-derived neuronal cultures expressing the Alzheimer’s disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

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