Poly IC Triggers a Cathepsin D- and IPS-1-Dependent Pathway to Enhance Cytokine Production and Mediate Dendritic Cell Necroptosis
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RIG-I-like receptors (RLRs) sense virus-derived RNA or polyinosinic-polycytidylic acid (poly IC) to exert antiviral immune responses. Here, we examine the mechanisms underlying the adjuvant effects of poly IC. Poly IC was taken up by dendritic cells (DCs), and it induced lysosomal destabilization, which, in turn, activated an RLR-dependent signaling pathway. Upon poly IC stimulation, cathepsin D was released into the cytoplasm from the lysosome to interact with IPS-1, an adaptor molecule for RLRs. This interaction facilitated cathepsin D cleavage of caspase 8 and the activation of the transcription factor NF-κB, resulting in enhanced cytokine production. Further recruitment of the kinase RIP-1 to this complex initiated the necroptosis of a small number of DCs. HMGB1 released by dying cells enhanced IFN-β production in concert with poly IC. Collectively, these findings suggest that cathepsin D-triggered, IPS-1-dependent necroptosis is a mechanism that propagates the adjuvant efficacy of poly IC.
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Synthetic TLR3 ligand polyI:C or co-administration of low-dose LPS and caspase inhibitor Z-VAD-fmk trigger necroptosis in dendritic cells or microglial cells, respectively.
“Accordingly, the synthetic TLR3 ligand polyinosinic-polycytidylic acid (polyI:C) or the co-administration of low-dose LPS and the caspase inhibitor Z-VAD-fmk trigger necroptosis in dendritic cells (DCs) [518] or microglial cells [519], respectively.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [518]
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References 68 · Cited by 103
- Authors
- Zou, J., Kawai, T., Tsuchida, T., Kozaki, T., Tanaka, H., Shin, K.-S., Kumar, H., & Akira, S.
- Affiliations
- Immunology Frontier Research Center, The University of Osaka (JP)
- Yamagata University (JP)
- Jeju National University Hospital (KR)
- Indian Institute of Science Education and Research, Bhopal (IN)
- Corresponding author
- Kawai, Taro
- Akira, Shizuo
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 38
- Issue
- 4
- Pages
- 717-728
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2070740895
- Cited by
- 103
- References
- 68
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 11 · 2015: 6 · 2014: 11 · 2013: 3
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (20002008)
- National Institute of Allergy and Infectious Diseases (P01AI070167)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- poly(I:C), cathepsin D, IPS-1, RIG-I-like receptors, lysosomal destabilization, caspase-8, NF-κB activation, HMGB1, interferon-beta, cytokine production, vaccine adjuvants, antiviral innate immunity
- MeSH terms
- Animals, Cathepsin D, Cells, Cultured, Dendritic Cells, Immunity, Innate, Mice, Inbred C57BL, Mice, Inbred Strains, Necrosis, Poly I-C, Protein Binding, Signal Transduction, Cytokines, Mice, Knockout, GTPase-Activating Proteins, HMGB1 Protein, Adaptor Proteins, Signal Transducing, Mice, Immunomodulation
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