Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis

Abstract Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocy...

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Autores principales:	Peter Järver, Aleksandra Dondalska, Candice Poux, AnnSofi Sandberg, Joseph Bergenstråhle, Annette E. Sköld, Nathalie Dereuddre-Bosquet, Fréderic Martinon, Sandra Pålsson, Eman Zaghloul, David Brodin, Birgitta Sander, Kim A. Lennox, Mark A. Behlke, Samir EL-Andaloussi, Janne Lehtiö, Joakim Lundeberg, Roger LeGrand, Anna-Lena Spetz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Clathrin-mediated Endocytosis (CME) Endosomal TLR Endocytic Uptake Signaling Endosomes Inhibiting TLR4 Activation Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8ee60f6cd9e941b7b20a1654b77636dc
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spelling	oai:doaj.org-article:8ee60f6cd9e941b7b20a1654b77636dc2021-12-02T15:08:41ZSingle-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis10.1038/s41598-018-33960-42045-2322https://doaj.org/article/8ee60f6cd9e941b7b20a1654b77636dc2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33960-4https://doaj.org/toc/2045-2322Abstract Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream of TLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.Peter JärverAleksandra DondalskaCandice PouxAnnSofi SandbergJoseph BergenstråhleAnnette E. SköldNathalie Dereuddre-BosquetFréderic MartinonSandra PålssonEman ZaghloulDavid BrodinBirgitta SanderKim A. LennoxMark A. BehlkeSamir EL-AndaloussiJanne LehtiöJoakim LundebergRoger LeGrandAnna-Lena SpetzNature PortfolioarticleClathrin-mediated Endocytosis (CME)Endosomal TLREndocytic UptakeSignaling EndosomesInhibiting TLR4 ActivationMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clathrin-mediated Endocytosis (CME) Endosomal TLR Endocytic Uptake Signaling Endosomes Inhibiting TLR4 Activation Medicine R Science Q
spellingShingle	Clathrin-mediated Endocytosis (CME) Endosomal TLR Endocytic Uptake Signaling Endosomes Inhibiting TLR4 Activation Medicine R Science Q Peter Järver Aleksandra Dondalska Candice Poux AnnSofi Sandberg Joseph Bergenstråhle Annette E. Sköld Nathalie Dereuddre-Bosquet Fréderic Martinon Sandra Pålsson Eman Zaghloul David Brodin Birgitta Sander Kim A. Lennox Mark A. Behlke Samir EL-Andaloussi Janne Lehtiö Joakim Lundeberg Roger LeGrand Anna-Lena Spetz Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
description	Abstract Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream of TLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.
format	article
author	Peter Järver Aleksandra Dondalska Candice Poux AnnSofi Sandberg Joseph Bergenstråhle Annette E. Sköld Nathalie Dereuddre-Bosquet Fréderic Martinon Sandra Pålsson Eman Zaghloul David Brodin Birgitta Sander Kim A. Lennox Mark A. Behlke Samir EL-Andaloussi Janne Lehtiö Joakim Lundeberg Roger LeGrand Anna-Lena Spetz
author_facet	Peter Järver Aleksandra Dondalska Candice Poux AnnSofi Sandberg Joseph Bergenstråhle Annette E. Sköld Nathalie Dereuddre-Bosquet Fréderic Martinon Sandra Pålsson Eman Zaghloul David Brodin Birgitta Sander Kim A. Lennox Mark A. Behlke Samir EL-Andaloussi Janne Lehtiö Joakim Lundeberg Roger LeGrand Anna-Lena Spetz
author_sort	Peter Järver
title	Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
title_short	Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
title_full	Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
title_fullStr	Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
title_full_unstemmed	Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
title_sort	single-stranded nucleic acids regulate tlr3/4/7 activation through interference with clathrin-mediated endocytosis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/8ee60f6cd9e941b7b20a1654b77636dc
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Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis

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