Human ß-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.
PLoS Genet
; 11(12): e1005673, 2015 Dec.
Article
en En
| MEDLINE
| ID: mdl-26646717
ABSTRACT
Human ß-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six ß-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-ß in response to the viral ligand mimic polyinosinicpolycytidylic acid (polyIC) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyIC alone, mice injected with both hBD3 peptide and polyIC also showed an enhanced increase in Interferon-ß. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-ß, and challenge with polyIC further increased this response. HBD3 peptide increased uptake of polyIC by macrophages, however the cellular response and localisation of polyIC in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyIC do not co-localise, but in the presence of hBD3 less polyIC localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyIC-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyIC implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Psoriasis
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Beta-Defensinas
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Proteínas Adaptadoras del Transporte Vesicular
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Proteínas Adaptadoras Transductoras de Señales
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Receptor Toll-Like 3
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ARN Helicasas DEAD-box
Límite:
Animals
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Humans
Idioma:
En
Revista:
PLoS Genet
Asunto de la revista:
GENETICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Reino Unido