The Danger Signal S100B Integrates Pathogen– and Danger–Sensing Pathways to Restrain Inflammation
Open Access
- 10 March 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 7 (3), e1001315
- https://doi.org/10.1371/journal.ppat.1001315
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. Inflammation results from recognition of invading microorganisms through pathogen–associated molecular patterns (PAMPs) and from reaction to tissue damage–associated molecular patterns (DAMPs). Despite the identification of specific signaling pathways negatively regulating responses to PAMPs or DAMPs, the unexpected convergence of molecular pathways responsible for recognition of either one raised the question of whether and how the host discriminates between the two distinct molecular patterns. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen– and danger–sensing pathways to restrain inflammation in Aspergillus fumigatus infection. By disclosing protective mechanisms that ensure prompt control of the pathogen and inflammation, our results may help to explain why humans inhale hundreds of Aspergillus conidia without adverse consequences.Keywords
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