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.
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
Tatiana
T
Gianni
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
Gabriella
G
Campadelli-Fiume
D001419:Bacteria / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D009474:Neurons / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
D039302:Integrin alphaVbeta3; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt