Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma

Podolsky, Michael A.; Solomos, Andreas C.; Durso, Lisa C.; Evans, Suzette M.; Rall, Glenn F.; Rose, R. Wesley

doi:10.1016/j.jneuroim.2012.06.006

Cited by 15 publications

(18 citation statements)

References 30 publications

(38 reference statements)

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“…IFNγ also blocks cell cycle progression in the G0/G1 phase in astrocytes in a STAT1‐dependent manner, with minimal induction of apoptosis (O'Donnell et al, ). In contrast, primary hippocampal neurons express low endogenous levels of STAT1, which is associated with delayed but sustained engagement of JAKs with IFNGR and prolonged STAT1 phosphorylation (Podolsky et al, ; Rose et al, ). IFNγ also induces protective signaling pathways in neurons that are STAT1‐independent.…”

Section: Discussionmentioning

confidence: 99%

“…Though hundreds of IFN‐responsive genes are known, the profile of antiviral gene expression, and the subsequent effects on cellular function and survival, is dependent partially upon cell type. Within the CNS, specific neural cells display unique signaling profiles and cellular responses upon IFNγ stimulation, dependent upon the endogenous expression of the JAK‐STAT1 proteins (Burdeinick‐Kerr et al, ; O'Donnell et al, ; Podolsky et al, ; Rose et al, ; Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

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The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

Kulkarni

Scully

O’Donnell

2016

J of Neuroscience Research

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Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFNγ), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules. Here, we show that IFNγ inhibits proliferation of primary NSPCs through dephosphorylation of the tumor suppressor Retinoblastoma protein (pRb), which is dependent on activation of signal transducers and activators of transcription‐1 (STAT1) signaling pathways. Our results show i) IFNγ inhibits neurosphere growth and proliferation rate in a dose‐dependent manner; ii) IFNγ blocks cell cycle progression through a late‐stage G1/S phase restriction; iii) IFNγ induces phosphorylation and expression of STAT1 and STAT3; iv) IFNγ decreases cyclin E/cdk2 expression and reduces phosphorylation of cyclin D1 and pRb on serine residue 795; and v) the effects of IFNγ on NSPC proliferation, cell cycle protein expression, and pRb phosphorylation are STAT1‐dependent. These data define a mechanism by which IFNγ could contribute to a reduction in NSPC proliferation in inflammatory conditions. Further delineation of the effects of inflammatory cytokines on NSPC growth could improve our understanding of how CNS infections and other inflammatory events disrupt brain development and NSPC function. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

Kulkarni

Scully

O’Donnell

2016

J of Neuroscience Research

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“…Although these neurons have low basal expression of many ISGs, their induction is appreciable after viral infection. The role or evolutionary advantage of lower homeostatic expression of key signaling molecules in neurons remains to be clearly defined (31,36). While the well-studied ISG product Bst2 was significantly induced in primary neurons and in vivo, this protein appears to be dispensable for survival after neurotropic infection.…”

Section: Discussionmentioning

confidence: 99%

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Holmgren

Miller

Cavanaugh

et al. 2015

J Virol

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In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis. IMPORTANCE Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamen-tally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections. Many of the foundational principles in immunology have resulted from basic observations of virus-cell interactions, including the induction and antiviral function of both type I and type II interferons (IFNs) (reviewed in references 1, 2, and 3). Viral infection of a cell typically results in cellular production and secretion of type I IFNs, which can then bind to cell surface receptors in a paracrine and autocrine fashion, leading to synthesis of interferon-stimulated genes (ISGs). These ISGs, in turn, aid in clearing the viral infection by directly cleaving viral nucleic acids, triggering cellular apoptosis, inducing autophagy, upregulating major histocompatibility complex (MHC) class I expression to aid in CD8 ϩ T cell-mediated cytotoxicity, and preventing viral egress. Moreover, the induction of type I IFN contributes to the recruitment of adaptive immune effectors to infected sites, which further promotes viral clearance.One ISG that is highly induced following infection by many viruses, and in response to both type I and II IFN signaling, is the gene for bone marrow stromal antigen 2 (Bst2; also known a...

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“…Delayed STAT activation coincides with delayed expression of traditional ISGs 41 . The protracted interval between receptor binding and STAT activation may be due to a greatly reduced basal expression of STATs in these hippocampal neurons, as compared with other cell types [40][41][42] . Interestingly, lower homeostatic STAT expression is not unique to neurons but has also been observed in another non-renewable cell type, cardiac myocytes 43 .…”

Section: Type I Interferon Signallingmentioning

confidence: 93%

Keeping it in check: chronic viral infection and antiviral immunity in the brain

2016

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It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response — when combined with the unique anatomy and physiology of the CNS — provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.

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Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma

Cited by 15 publications

References 30 publications

The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Keeping it in check: chronic viral infection and antiviral immunity in the brain

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