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RIPK1-Caspase-8-Mediated Inflammation and Cell Death During Bacterial Infection and Neurodegenerative Disease
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JZ Dissertation full.revision. ...
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2026-10-16
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Doctoral Dissertation
Authors
Zhang, BoyaoFaculty Advisor
Egil LienAcademic Program
Interdisciplinary Graduate ProgramDocument Type
Doctoral DissertationPublication Date
2024-09-19
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Show full item recordAbstract
Inflammation and cell death play crucial roles in acute infection and neurodegenerative disease. Receptor interacting serine/threonine kinases 1 (RIPK1) and caspase-8 orchestrate the crosstalk among inflammation, apoptosis, pyroptosis, and necroptosis. Thus, careful regulation of these multimodal proteins is critical for proper immune function and tissue homeostasis. We identified splicing factor Raver1 as a key regulator of RIPK1 expression and function. Loss of Raver1 promotes alternative splicing on Ripk1, resulting in a truncated, dysfunctional variant (Splice I) and reduced functional RIPK1 levels. Raver1-deficient primary macrophages display impaired caspase-8-mediated pyroptosis and IL-1ß/IL-18 release in response to Yersinia or TAK1-blockade. Consequently, Raver1-deficient mice exhibit compromised antimicrobial responses and increased susceptibility to Yersinia infection. Additionally, Raver1 promotes the expression and function of the C-type lectin receptor Mincle via RIPK1 control. Our study highlights the role of Raver1 in modulating innate immune responses and a new layer of regulation during pyroptosis. RIPK1 activation is implicated in Alzheimer’s disease (AD), but its mechanisms in regulating neuroinflammation are not fully understood. Here we demonstrate that in primary microglia, neuroinflammatory stimuli enable RIPK1 to control caspase-8-mediated pyroptosis and IL-1ß release, as well as RIPK3-dependent necroptosis. Moreover, genetic deficiencies in RIPK1, RIPK3, MLKL, or caspase-8 differentially ameliorate neuroinflammation and spatial memory deficits in aged APP/PS1 mice, an AD model. These findings suggest that RIPK1 coordinates caspase-8 signaling with necroptosis axis in AD. Collectively, my work elucidates how RIPK1 orchestrates an intricate inflammatory cell death network during pathogenic infection and neurodegeneration.DOI
10.13028/dfj8-3652Permanent Link to this Item
http://hdl.handle.net/20.500.14038/53871Rights
Copyright © 2024 Boyao ZhangDistribution License
All Rights Reservedae974a485f413a2113503eed53cd6c53
10.13028/dfj8-3652