title: The danger signal S100B integrates pathogen- and danger-sensing pathways to restrain inflammation.
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.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Sorci
authors.forename: Gloria
authors.initials: G
authors.lastname: Giovannini
authors.forename: Francesca
authors.initials: F
authors.lastname: Riuzzi
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bonifazi
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Silvia
authors.initials: S
authors.lastname: Zagarella
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Rosario
authors.initials: R
authors.lastname: Donato
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001230:Aspergillus / Q000472:pathogenicity / Q000502:physiology*; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism*; D055732:Pulmonary Aspergillosis / Q000378:metabolism / Q000382:microbiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2