An integrin axis induces IFN-beta production in plasmacytoid dendritic cells

Type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) has been mainly studied in the context of Toll-like receptor (TLR) activation. In the current report, we reveal that, in the absence of TLR activation, the integrin-binding SLAYGLR motif of secreted osteopontin (sOpn) induces IFN-beta production in murine pDCs. This process is mediated by alpha 4 beta 1 integrin, indicating that integrin triggering may act as a subtle danger signal leading to IFN-beta induction. The SLAYGLR-mediated alpha 4 integrin/IFN-beta axis is MyD88 independent and operates via a PI3K/mTOR/IRF3 pathway. Consequently, SLAYGLR-treated pDCs produce increased levels of type I IFNs following TLR stimulation. Intratumoral administration of SLAYGLR induces accumulation of IFN-beta-expressing pDCs and efficiently suppresses melanoma tumor growth. In this process, pDCs are crucial. Finally, SLAYGLR enhances pDC development from bone marrow progenitors. These findings open new questions on the roles of sOpn and integrin alpha 4 during homeostasis and inflammation. The newly identified integrin/IFN-beta axis may be implicated in a wide array of immune responses.