Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4.
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.
Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX, USA.
Valentine Ongeri
VO
Millien
Wen
W
Lu
Joanne
J
Shaw
Xiaoyi
X
Yuan
Garbo
G
Mak
Luz
L
Roberts
Li-Zhen
LZ
Song
J Morgan
JM
Knight
Chad J
CJ
Creighton
Amber
A
Luong
Farrah
F
Kheradmand
David B
DB
Corry
D000818:Animals; D001234:Aspergillus niger / Q000254:growth & development / Q000276:immunology*; D001236:Aspergillus oryzae / Q000201:enzymology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D007113:Immunity, Innate; D008024:Ligands; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000276:immunology / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005340:Fibrinogen; D010447:Peptide Hydrolases