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

Immunology and Cell Biology
Sara J ThygesenK J Stacey

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.

References

Oct 1, 1981·European Journal of Immunology·J M Austyn, S Gordon
Feb 15, 1997·Nucleic Acids Research·C J CoolidgeJ G Patton
Aug 3, 2000·Seminars in Arthritis and Rheumatism·A BorchersM E Gershwin
Jul 13, 2002·Science·William G FairbrotherChristopher B Burge
Oct 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Gene YeoChristopher B Burge
Jan 13, 2006·Nature·Sanjeev MariathasanVishva M Dixit
Sep 20, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·David P SesterMatthew J Sweet
Dec 14, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·P L HardingS D Wilton
Sep 25, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Annemieke Aartsma-RusGert-Jan B van Ommen
Mar 25, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sue FletcherSteve D Wilton
Jul 14, 2011·Genome Research·Timothy Sterne-WeilerJeremy R Sanford
Mar 1, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·John C ScatizziDwight H Kono
Aug 9, 2012·BMC Evolutionary Biology·Jasmyn A CridlandKatryn J Stacey
Mar 26, 2013·Human Gene Therapy·Taeyoung Koo, Matthew J Wood
May 7, 2013·Cell Death and Differentiation·V SagulenkoK J Stacey
May 15, 2013·EMBO Molecular Medicine·Franz Bauernfeind, Veit Hornung
Feb 4, 2014·Experimental Cell Research·Marcel Veltrop, Annemieke Aartsma-Rus
Sep 17, 2014·Molecular Therapy. Nucleic Acids·Lorena Gallego-VillarLourdes R Desviat
Jun 28, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·David P SesterKatryn J Stacey

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Citations

Oct 19, 2016·Nucleic Acid Therapeutics·João Casaca-CarreiraAli Jahanshahi
Jul 28, 2018·Immunology and Cell Biology·Sara J ThygesenKatryn J Stacey
Jan 9, 2017·European Heart Journal·Ruben G de BruinEric P van der Veer

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