CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging

Kaya, Tuğberk; Mattugini, Nicola; Liu, Lu; Ji, Hao; Cantuti-Castelvetri, Ludovico; Weng, Jianping; Schifferer, Martina; Groh, Janos; Martini, Rudolf; Besson-Girard, Simon; Kaji, Shunsuke; Liesz, Arthur; Gökçe, Özgün; Simons, Mikael

doi:10.1038/s41593-022-01183-6

Cited by 108 publications

(80 citation statements)

References 72 publications

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“…Degradation of myelin sheaths of the neuronal system is accompanied by inflammatory processes closely related to aging in the brain (Kaya et al, 2022;Safaiyan et al, 2016), which in turn is increasingly associated which COVID-19 (Mavrikaki et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Schweizer

Schaller

Zwiebel

et al. 2022

Preprint

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SARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tissues. The first layer of response in all tissues was dominated by circulating inflammatory molecules. To discriminated between these systemic and true tissue-specific effects, we developed an analysis pipeline revealing that proteome alterations reflect extensive tissue damage, mostly similar to non-COVID diffuse alveolar damage. The next most affected organs were kidney and liver, while the lymph-vessel system was also strongly affected. Finally, secondary inflammatory effects of the brain correlated with receptor rearrangements and the degradation of neuronal myelin. Our results establish MS-based tissue proteomics as a promising strategy to inform organ-specific therapeutic interventions following COVID-19 infections.

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Section: Discussionmentioning

confidence: 99%

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Schweizer

Schaller

Zwiebel

et al. 2022

Preprint

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“…The loss of axonal integrity in white matter in the aging brain and in various neurodegenerative diseases is increasingly considered to result from homeostatic dysfunctions in the axon-OL unit 6,7,14,21,[54][55][56][57] . Yet, how OLs interact with and support myelinated axons throughout life is still enigmatic.…”

Section: Discussionmentioning

confidence: 99%

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

Looser

Ravotto

Jung³

et al. 2022

Preprint

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The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs), which is essential for brain function. However, the mechanisms by which OLs detect axonal spiking and rapidly control axon-OL metabolic coupling are largely unknown. Here, we combine optic nerve electrophysiology and two-photon imaging to study activity-dependent calcium (Ca2+) dynamics in OLs and metabolite fluxes in myelinated axons. Both high-frequency axonal firing and extracellular potassium (K+) elevations trigger a fast Ca2+response in OLs that is facilitated by barium-sensitive, inwardly rectifying K+channels. Using OL-specific Kir4.1 knockout mice (Kir4.1 cKO) we now demonstrate that, in addition to being crucial for K+clearance, oligodendroglial Kir4.1 regulates axonal energy metabolism and long-term axonal integrity. Before the manifestation of axonal damage, we observed reduced glucose transporter GLUT1 and monocarboxylate transporter MCT1 expression in myelin of young Kir4.1 cKO mice, suggesting early deficits in metabolite supply to axons. Strikingly, we found lower resting lactate levels and activity-induced lactate surges in optic nerve axons of young Kir4.1 cKO mice. Moreover, both axonal glucose uptake and consumption were hampered in the absence of oligodendroglial Kir4.1, uncovering a new role of OLs in regulating axonal glucose metabolism. Our findings reveal a novel model of axon-OL signaling and metabolic coupling in which OLs detect high-frequency axonal activity through K+signaling, which is critical in adjusting the axon-OL metabolic unit and in preserving long-term axonal health.

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“…Within the CNS, it is well-established that activated microglia express MHC-II (McGeer et al, 1988; Vass and Lassmann, 1990), but prior studies of MHC-II expression in mouse oligodendrocytes and astrocytes have yielded conflicting results (Falcão et al, 2018; Rostami et al, 2020; Stüve et al, 2002; Vass and Lassmann, 1990). In the context of MS, single cell RNA-seq in mouse models (Falcão et al, 2018; Kaya et al, 2022) and human brain tissue (Jäkel et al, 2019) identified subsets of mature oligodendrocytes that express IFN-inducible genes, including MHC-I and MHC-II genes, although only MHC-I associated signals was observed in human neuropathology (Höftberger et al, 2004). Our results suggest that acute stimulation with IFN-γ elicits the transcriptional upregulation of MHC-II genes only in microglia ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

Sulzer

Hobson

Stanley³

et al. 2022

Preprint

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Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it remains unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We find that IFN-γ induces cellular proliferation and expression of MHC-II and associated genes only in microglia. However, IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were conserved across neurons and glia, with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, while no neuron-specific responses to IFN-γ were observed. Using mutant mice to selectively delete the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, we demonstrate that dopaminergic neurons respond directly to IFN-γ. Our results suggest that most neurons are capable of responding directly to IFN-γ and upregulating MHC-I and related genes in vivo, but their expression amplitude and repertoire is limited compared to oligodendrocytes, astrocytes, and microglia.

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CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging

Cited by 108 publications

References 72 publications

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

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