the danger signal s100b integrates pathogen– and danger–sensing pathways to restrain inflammation危险信号s100b集成了病原体,danger-sensing途径抑制炎症.pdfVIP

The Danger Signal S100B Integrates Pathogen– and Danger–Sensing Pathways to Restrain Inflammation Guglielmo Sorci., Gloria Giovannini., Francesca Riuzzi, Pierluigi Bonifazi, Teresa Zelante, Silvia Zagarella, Francesco Bistoni, Rosario Donato, Luigina Romani* Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy Abstract Humans inhale hundreds of Aspergillus conidia without adverse consequences. Powerful protective mechanisms may ensure prompt control of the pathogen and inflammation. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen– and danger–sensing pathways to restrain inflammation. Upon forming complexes with TLR2 ligands, S100B inhibited TLR2 via RAGE, through a paracrine epithelial cells/neutrophil circuit that restrained pathogen-induced inflammation. However, upon binding to nucleic acids, S100B activated intracellular TLRs eventually resolve danger-induced inflammation via transcriptional inhibition of S100B. Thus, the spatiotemporal regulation of TLRs and RAGE by S100B provides evidence for an evolving braking circuit in infection whereby an endogenous danger protects against pathogen–induced inflammation and a pathogen–sensing mechanism resolves danger–induced inflammation. Citation: Sorci G, Giovannini G, Riuzzi F, Bonifazi P, Zelante T, et al. (2011) The Danger Signal S100B Integrates Pathogen– and Danger–Sensing Pathways to Restrain Inflammation. PLoS Pathog 7(3): e1001315. doi:10.1371/journal.ppat.1001315 Editor: Stuart M. Levitz, University of Massachusetts Medical School, United States of America Received October 12, 2010; Accepted February 8, 2011; Published March 10, 2011 Copyright: 2011 Sorci et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits un