PLoS Pathogens · 2011 · 98 citations · 45 references
Life SciencesImmunologyMolecular BiologyInflammationInnate ImmunitySignal TransductionInflammatory SignalingInnate Immune ActivationInnate Immune ReceptorsInnate Immune ResponseInnate Immune Signaling PathwaysToll-like ReceptorsDanger-associated Molecular Pattern SignalingFungal Infection ImmunityFungal Infection InflammationHost Immune Response To FungiInnate Immune Signaling AdaptorsNucleotide-binding Oligomerization Domain-like Receptor SignalingPathogen-associated Molecular Pattern SensingS100b Protein
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.
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