Paradoxical roles for programmed cell death signaling during viral infection of the central nervous system

Angel, Juan P.; Daniels, Brian P.

doi:10.1016/j.conb.2022.102629

Cited by 7 publications

(8 citation statements)

References 70 publications

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“…Many studies have now firmly established the importance of RIPK3 in promoting host defense through mechanisms independent of its canonical role in necroptosis (16)(17)(18)(19)(20)(21). However, these necroptosis-independent functions appear to vary significantly by disease state, including CNS infection with distinct neuroinvasive flaviviruses (47,48). We and others previously showed that the primary role for RIPK3 in restricting WNV encephalitis was the induction of chemokine expression and the recruitment of antiviral leukocytes into the infected CNS (16).…”

Section: Discussionmentioning

confidence: 99%

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Lindman

Angel

Estevez

et al. 2023

Preprint

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Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3-mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS.

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Section: Discussionmentioning

confidence: 99%

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Lindman

Angel

Estevez

et al. 2023

Preprint

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“…To date, these cell death-independent functions have primarily been pro-inflammatory in nature. Within the CNS, we and others have shown that RIPK3 signaling is a central coordinator of neuroinflammatory activation, with both protective and pathologic consequences during neurologic disease states ( 21, 22, 45 ). Despite this understanding, cell-type specific functions for RIPK3 within the CNS have not been carefully delineated.…”

Section: Discussionmentioning

confidence: 94%

“…Recent work from our laboratory and others has identified a significant role for receptor interacting protein kinase-3 (RIPK3) in coordinating neuroimmune responses to flavivirus infections in the CNS (21,22). RIPK3 is canonically associated with a form of lytic programmed cell death known as "necroptosis," although a growing body of work has now defined extensive functions for RIPK3 that occur independently of cell death (23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors

Lindman,

Estevez,

Marmut

et al. 2024

Preprint

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Flaviviruses pose a significant threat to public health due to their ability to infect the central nervous system (CNS) and cause severe neurologic disease. Astrocytes play a crucial role in the pathogenesis of flavivirus encephalitis through their maintenance of blood-brain barrier (BBB) integrity and their modulation of immune cell recruitment and activation within the CNS. We have previously shown that receptor interacting protein kinase-3 (RIPK3) is a central coordinator of neuroinflammation during CNS viral infection, a function that occurs independently of its canonical function in inducing necroptotic cell death. To date, however, roles for necroptosis-independent RIPK3 signaling in astrocytes are poorly understood. Here, we use mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an unexpected anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes was required for host survival in multiple models of flavivirus encephalitis, where it restricted neuropathogenesis by limiting immune cell recruitment to the CNS. Transcriptomic analysis revealed that, despite inducing a traditional pro-inflammatory transcriptional program, astrocytic RIPK3 paradoxically promoted neuroprotection through the upregulation of serpins, endogenous protease inhibitors with broad immunomodulatory activity. Notably, intracerebroventricular administration of SerpinA3N in infected mice preserved BBB integrity, reduced leukocyte infiltration, and improved survival outcomes in mice lacking astrocytic RIPK3. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation and suggests new therapeutic targets for the treatment of flavivirus encephalitis.

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“…Our work also adds new insight to our expanding understanding of the adaptation of innate immunity in neurons, whose unique and vital roles in organismal health necessitate tight regulation of cell fate and survival. Extensive previous work has shown that neurons are resistant to programmed cell death 65 , including RIPK3-mediated necroptosis 10 . We and others have shown that the cell-death independent functions of RIPK3 are critical for host control of CNS viral infection through the well-established functions of this kinase in promoting immunological gene expression [13][14][15] .…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has described specialized adaptations of several innate immune processes in neurons. For example, we and others have described cell death-independent functions for Receptor interacting kinase-3 (RIPK3), the canonical inducer of a form of programmed cell death termed "necroptosis" [10][11][12] . In the setting of neurotropic flavivirus infection, activation of RIPK3 does not engage the necroptotic executioner molecule mixed lineage kinase domain-like protein (MLKL), but rather coordinates a dramatic shift in neuronal transcription and metabolism to induce an antiviral state in the absence of cell death [13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during CNS viral infection

Estevez,

Buckley,

Panzera

et al. 2024

Preprint

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While recent work has identified roles for immune mediators in the regulation of neural activity, the capacity for cell intrinsic innate immune signaling within neurons to influence neurotransmission remains poorly understood. However, the existing evidence linking immune signaling with neuronal function suggests that modulation of neurotransmission may serve previously undefined roles in host protection during infection of the central nervous system. Here, we identify a specialized function for RIPK3, a kinase traditionally associated with necroptotic cell death, in preserving neuronal survival during neurotropic flavivirus infection through the suppression of excitatory neurotransmission. We show that RIPK3 coordinates transcriptomic changes in neurons that suppress neuronal glutamate signaling, thereby desensitizing neurons to excitotoxic cell death. These effects occur independently of the traditional functions of RIPK3 in promoting necroptosis and inflammatory transcription. Instead, RIPK3 promotes phosphorylation of the key neuronal regulatory kinase CaMKII, which in turn activates the transcription factor CREB to drive a neuroprotective transcriptional program and suppress deleterious glutamatergic signaling. These findings identify an unexpected function for a canonical cell death protein in promoting neuronal survival during viral infection through the modulation of neuronal activity, highlighting new mechanisms of neuroimmune crosstalk.

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Paradoxical roles for programmed cell death signaling during viral infection of the central nervous system

Cited by 7 publications

References 70 publications

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors

RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during CNS viral infection

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