Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4

Science. 2013 Aug 16;341(6147):792-6. doi: 10.1126/science.1240342.

Abstract

Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. These outcomes were induced by proteinase cleavage of the clotting protein fibrinogen, yielding fibrinogen cleavage products that acted as TLR4 ligands on airway epithelial cells and macrophages. Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillus niger / growth & development
  • Aspergillus niger / immunology*
  • Aspergillus oryzae / enzymology
  • Bronchoalveolar Lavage Fluid / cytology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Fibrinogen / metabolism*
  • Immunity, Innate
  • Ligands
  • Macrophage Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Peptide Hydrolases / immunology
  • Peptide Hydrolases / metabolism*
  • Respiratory Hypersensitivity / immunology*
  • Respiratory Hypersensitivity / metabolism*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Th2 Cells / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Ligands
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Fibrinogen
  • Peptide Hydrolases

Associated data

  • GEO/GSE48609