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


RESULTS
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)β(1). The mechanism for integrin α(3)β(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.


CONCLUSIONS
Here we identify integrin α(3)β(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)β(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)β(1) serves as a mechanism for modulating inflammatory responses.
Marre
Meghan L
ML
Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Petnicki-Ocwieja
Tanja
T
DeFrancesco
Alicia S
AS
Darcy
Courtney T
CT
Hu
Linden T
LT
D025065:Borrelia burgdorferi / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D055666:Lipopeptides / Q000378:metabolism*; D008193:Lyme Disease / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D039201:Integrin alpha3beta1; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2