Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments.

2.50
Hdl Handle:
http://hdl.handle.net/10033/99555
Title:
Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments.
Authors:
Dietrich, Nicole; Lienenklaus, Stefan; Weiss, Siegfried; Gekara, Nelson O
Abstract:
BACKGROUND: Toll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways. Interestingly, by microscopy we demonstrate that although a cell surface receptor, TLR2 dependent induction of type I interferons occurs in endolysosomal compartments where it is translocated to upon ligand engagement. Furthermore, we could show that blocking receptor internalization or endolysosomal acidification inhibits the ability of TLR2 to trigger the induction type I interferon but not pro-inflammatory responses. CONCLUSION/SIGNIFICANCE: The results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.
Affiliation:
Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Citation:
Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments. 2010, 5 (4):e10250 PLoS ONE
Journal:
PloS one
Issue Date:
2010
URI:
http://hdl.handle.net/10033/99555
DOI:
10.1371/journal.pone.0010250
PubMed ID:
20422028
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the research group molecular Immunology (MOLI)

Full metadata record

DC FieldValue Language
dc.contributor.authorDietrich, Nicoleen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorWeiss, Siegfrieden
dc.contributor.authorGekara, Nelson Oen
dc.date.accessioned2010-05-21T11:17:49Z-
dc.date.available2010-05-21T11:17:49Z-
dc.date.issued2010-
dc.identifier.citationMurine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments. 2010, 5 (4):e10250 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid20422028-
dc.identifier.doi10.1371/journal.pone.0010250-
dc.identifier.urihttp://hdl.handle.net/10033/99555-
dc.description.abstractBACKGROUND: Toll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways. Interestingly, by microscopy we demonstrate that although a cell surface receptor, TLR2 dependent induction of type I interferons occurs in endolysosomal compartments where it is translocated to upon ligand engagement. Furthermore, we could show that blocking receptor internalization or endolysosomal acidification inhibits the ability of TLR2 to trigger the induction type I interferon but not pro-inflammatory responses. CONCLUSION/SIGNIFICANCE: The results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.en
dc.language.isoenen
dc.titleMurine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments.en
dc.typeArticleen
dc.contributor.departmentMolecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.en
dc.identifier.journalPloS oneen
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