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SIDT1 plays a key r...
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Morell, MariaKarolinska Institutet
(author)
SIDT1 plays a key role in type I IFN responses to nucleic acids in plasmacytoid dendritic cells and mediates the pathogenesis of an imiquimod-induced psoriasis model
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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Elsevier,2022
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-476800
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-476800URI
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https://doi.org/10.1016/j.ebiom.2021.103808DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:149646096URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Background Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natural IFN-producing cells, the plasmacytoid dendritic cells (pDC).Methods The function of SIDT1 in pDC was determined by silencing its expression in human primary pDC and GEN2.2 cell line. SIDT1 role in vivo was assessed using the imiquimod-induced psoriasis model in the SIDT1-deficient mice (sidt1-/-).Findings Silencing of SIDT1 in GEN2.2 led to a blockade of the IFN-I response after stimulation of TLR7 and TLR9, without affecting the pro-inflammatory responses or upregulation of maturation markers. We found that SIDT1 migrates from the ER to the endosomal and lysosomal compartments together with TLR9 after CpG stimulation, participating in the access of the TLR9-CpG complex to lysosome-related vesicles, and therefore mediating the activation of TBK1 and the nuclear migration of IRF7, but not of NF -KB. sidt1-/- mice showed a significant decrease in severity parameters of the imiquimod-induced acute psoriasis-like model, associated with a decrease in the production of IFN-I and IFN-dependent chemokines.Interpretation Our findings indicate that SIDT1 is at the cross-road between the IFN-I and the proinflammatory pathways and constitutes a promising drug target for psoriasis and other diseases mediated by IFN-I responses.
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Varela, NievesUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
(author)
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Castillejo-Lopez, CasimiroUppsala universitet,Klinisk diabetologi och metabolism,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab(Swepub:uu)cacas173
(author)
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Coppard, CelineUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
(author)
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Jose Luque, MariaUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
(author)
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Wu, Ying-YuOklahoma Med Res Fdn, Arthrit & Clin Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA
(author)
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Martin-Morales, NatividadUniv Granada, Sch Med, Dept Pathol, Granada, Spain.;Univ Granada, Sch Dent, Dept Oral Surg, Granada, Spain
(author)
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Perez-Cozar, FranciscoUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
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Gomez-Hernandez, GonzaloUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
(author)
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Kumar, RameshOklahoma Med Res Fdn, Arthrit & Clin Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA
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O'Valle, FranciscoUniv Granada, Sch Med, Dept Pathol, Granada, Spain.;Ibs GRANADA, Granada, Spain.;IBIMER Inst, Granada, Spain
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Alarcon-Riquelme, Marta E.Univ Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain.;Karolinska Inst, Inst Environm Med, Stockholm, Sweden
(author)
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Maranon, ConcepcionUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
(author)
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Karolinska InstitutetUniv Granada, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, GENYO, Avda Ilustrac 114, Granada 18016, Spain
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