The Epithelial αvβ3-Integrin Boosts the MYD88-Dependent TLR2 Signaling in Response to Viral and Bacterial Components

Tlr2 is a cell surface receptor which elicits an immediate response to a wide repertoire of bacteria and viruses. its response is usually thought to be proinflammatory rather than an antiviral. in monocytic cells tlr2 cooperates with coreceptors,e.g. cd14,cd36 and αmβ2-integrin. in an earlier work we showed that αvβ3-integrin acts in concert with tlr2 to elicit an innate response to hsv,and to lipopolysaccharide. this response is characterized by production of ifn-α and -β,a specific set of cytokines,and nf-κb activation. we investigated the basis of the cooperation between αvβ3-integrin and tlr2. we report that β3-integrin participates by signaling through y residues located in the c-tail,known to be involved in signaling activity. αvβ3-integrin boosts the myd88-dependent tlr2 signaling and irak4 phosphorylation in 293t and in epithelial,keratinocytic and neuronal cell lines. the replication of icp0minus hsv is greatly enhanced by dn versions of myd88,of akt – a hub of this pathway,or by β3integrin-silencing. αvβ3-integrin enables the recruitment of tlr2,mal,myd88 at lipid rafts,the platforms from where the signaling starts. the pamp of the hsv-induced innate response is the gh/gl virion glycoprotein,which interacts with αvβ3-integrin and tlr2 independently one of the other,and cross-links the two receptors. given the preferential distribution of αvβ3-integrin to epithelial cells,we propose that αvβ3-integrin serves as coreceptor of tlr2 in these cells. the results open the possibility that tlr2 makes use of coreceptors in a variety of cells to broaden its spectrum of activity and tissue specificity. © 2014 gianni,campadelli-fiume.