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Human integrin ?(3)?(1) regulates TLR2 recognition of lipopeptides from endosomal compartments.

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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/PRINCIPAL FINDINGS:

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, ?(3)?(1). The mechanism for integrin ?(3)?(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 ?(3)?(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 ?(3)?(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 ?(3)?(1) serves as a mechanism for modulating inflammatory responses.

PLoS One. 2010 Sep 22;5(9):e12871. doi: 10.1371/journal.pone.0012871. Research Support, N.I.H., Extramural

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