Selective fibrinogen cleavage by diverse proteinases initiates innate allergic and antifungal immunity through CD11b.

Selective fibrinogen cleavage by diverse proteinases initiates innate allergic and antifungal immunity through CD11b.

J Biol Chem. 2019 Apr 16;:

Authors: Landers CT, Tung HY, Knight JM, Madison MC, Wu Y, Zeng Z, Porter PC, Rodriguez A, Flick MJ, Kheradmand F, Corry DB

Abstract
Proteinases are essential drivers of allergic airway disease and innate antifungal immunity in part through their ability cleave the clotting factor fibrinogen (FBG) into fibrinogen cleavage products (FCPs) that signal through Toll like receptor 4 (TLR4).  However, the mechanism by which FCPs engage TLR4 remains unknown.  Here we show that the proteinases from Aspergillus melleus (PAM) and other allergenic organisms rapidly hydrolyze FBG to yield relatively few FCPs that drive distinct antifungal mechanisms through TLR4.  Functional FCPs, termed cryptokines, were characterized by rapid loss of the FBG alpha chain with substantial preservation of the beta and gamma chains, including a gamma chain sequence (Fibγ390-396) that binds the integrin Mac-1 (CD11b/CD18).  PAM-derived cryptokines could be generated from multiple FBG domains and the ability of cryptokines to induce fungistasis in vitroand innate allergic airway disease in vivo strongly depended on both Mac-1 and the Mac-1 binding domain of FBG (Fibγ390-396).  Our findings illustrate the essential concept of proteinase-activated immune responses (PAIRs) and for the first time link Mac-1, cryptokines and TLR4 to innate antifungal immunity and allergic airway disease.

PMID: 30992366 [PubMed – as supplied by publisher]

Source: Industry