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

• Published in: PloS one 2010-09, Vol.5 (9), p.e12871-e12871
• Main Authors: Marre, Meghan L, Petnicki-Ocwieja, Tanja, DeFrancesco, Alicia S, Darcy, Courtney T, Hu, Linden T
• Format: Article
• Language: English
• Subjects: Borrelia burgdorferi - immunology; Borrelia burgdorferi - metabolism; Endocytosis; Endosomes - genetics; Endosomes - metabolism; Humans; Integrin alpha3beta1 - genetics; Integrin alpha3beta1 - metabolism; Lipopeptides - metabolism; Lyme Disease - immunology; Lyme Disease - metabolism; Lyme Disease - microbiology; Macrophages - immunology; Macrophages - microbiology; Signal Transduction; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0012871

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. 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. 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.