Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
PLoS Pathog. 2011 Mar;7(3):e1001315. doi: 10.1371/journal.ppat.1001315. Epub 2011 Mar 10.
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.
人类吸入数以百计的曲霉分生孢子而没有不良后果。强大的保护机制可能确保对病原体和炎症的迅速控制。在这里，我们揭示了一种以前未知的机制，即危险分子 S100B 整合病原体和危险感应途径，以抑制炎症。S100B 与 TLR2 配体形成复合物后，通过上皮细胞/中性粒细胞旁分泌回路，通过 RAGE 抑制 TLR2，从而抑制病原体引起的炎症，该回路抑制 RAGE。然而，当与核酸结合时，S100B 激活细胞内 TLRs，最终通过 S100B 的转录抑制来解决危险引起的炎症。因此，S100B 对 TLR 和 RAGE 的时空调节为感染中的一个演变制动电路提供了证据，其中内源性危险可防止病原体引起的炎症，而病原体感应机制可解决危险引起的炎症。
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