Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production
Authors
Langjahr, PatriciaDiaz-Jimenez, David
De la Fuente, Marjorie
Rubio, Estefhany
Golenbock, Douglas T.
Bronfman, Francisca C.
Quera, Rodrigo
Gonzalez, Maria-Julieta
Hermoso, Marcela A.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Disease & ImmunologyDocument Type
Journal ArticlePublication Date
2014-12-22Keywords
MetalloproteasesMolting
Enzyme-linked immunoassays
Cell membranes
Flow cytometry
Monocytes
Immune response
Inflammation
Immunity
Immunology and Infectious Disease
Immunopathology
Metadata
Show full item recordAbstract
Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders.Source
PLoS One. 2014 Dec 22;9(12):e104624. doi: 10.1371/journal.pone.0104624. Link to article on publisher's siteDOI
10.1371/journal.pone.0104624Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39687PubMed ID
25531754Related Resources
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Copyright: © 2014 Langjahr et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0104624
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Except where otherwise noted, this item's license is described as <p>Copyright: © 2014 Langjahr et al. This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>