Human integrin α(3)ß(1) regulates TLR2 recognition of lipopeptides from endosomal compartments.
PLoS One
; 5(9): e12871, 2010 Sep 22.
Article
en En
| MEDLINE
| ID: mdl-20877569
ABSTRACT
BACKGROUND:
Toll-like receptor (TLR)-2/TLR1 heterodimers recognize bacterial lipopeptides and initiate the production of inflammatory mediators. Adaptors and co-receptors that mediate this process, as well as the mechanisms by which these adaptors and co-receptors function, are still being discovered. METHODOLOGY/PRINCIPALFINDINGS:
Using shRNA, blocking antibodies, and fluorescent microscopy, we show that U937 macrophage responses to the TLR2/1 ligand, Pam(3)CSK(4), are dependent upon an integrin, α(3)ß(1). The mechanism for integrin α(3)ß(1) involvement in TLR2/1 signaling is through its role in endocytosis of lipopeptides. Using inhibitors of endosomal acidification/maturation and physical tethering of the ligand, we show that the endocytosis of Pam(3)CSK(4) is necessary for the complete TLR2/1-mediated pro-inflammatory cytokine response. We also show that TLR2/1 signaling from the endosome results in the induction of different inflammatory mediators than TLR2/1 signaling from the plasma membrane. CONCLUSION/SIGNIFICANCE:
Here we identify integrin α(3)ß(1) as a novel regulator for the recognition of bacterial lipopeptides. We demonstrate that induction of a specific subset of cytokines is dependent upon integrin α(3)ß(1)-mediated endocytosis of the ligand. In addition, we address an ongoing controversy regarding endosomal recognition of bacterial lipopeptides by demonstrating that TLR2/1 signals from within endosomal compartments as well as the plasma membrane, and that downstream responses may differ depending upon receptor localization. We propose that the regulation of endosomal TLR2/1 signaling by integrin α(3)ß(1) serves as a mechanism for modulating inflammatory responses.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Endosomas
/
Enfermedad de Lyme
/
Borrelia burgdorferi
/
Integrina alfa3beta1
/
Receptor Toll-Like 2
/
Lipopéptidos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos