Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides

Thygesen, Sara J., Sester, David P., Cridland, Simon O., Wilton, Steve D. and Stacey, Katryn J. (2016) Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides. Immunology and Cell Biology, 94 5: 520-524. doi:10.1038/icb.2016.3

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Author Thygesen, Sara J.
Sester, David P.
Cridland, Simon O.
Wilton, Steve D.
Stacey, Katryn J.
Title Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides
Journal name Immunology and Cell Biology   Check publisher's open access policy
ISSN 0818-9641
1440-1711
Publication date 2016-02-02
Sub-type Article (original research)
DOI 10.1038/icb.2016.3
Open Access Status Not Open Access
Volume 94
Issue 5
Start page 520
End page 524
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2403 Immunology
1307 Cell Biology
Abstract Inflammasomes are molecular complexes activated by infection and cellular stress, leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) processing and cell death. The autoimmune NZB mouse strain does not express NLRP3, a key inflammasome initiator mediating responses to a wide variety of stimuli including endogenous danger signals, environmental irritants and a range of bacterial, fungal and viral pathogens. We have previously identified an intronic point mutation in the Nlrp3 gene from NZB mice that generates a splice acceptor site. This leads to inclusion of a pseudoexon that introduces an early termination codon and is proposed to be the cause of NLRP3 inflammasome deficiency in NZB cells. Here we have used exon skipping antisense oligonucleotides (AONs) to prevent aberrant splicing of Nlrp3 in NZB macrophages, and this restored both NLRP3 protein expression and NLRP3 inflammasome activity. Thus, the single point mutation leading to aberrant splicing is the sole cause of NLRP3 inflammasome deficiency in NZB macrophages. The NZB mouse provides a model for addressing a splicing defect in macrophages and could be used to further investigate AON design and delivery of AONs to macrophages in vivo.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 05 Feb 2016, 20:35:09 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences