Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells

Abstract

The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-α (IFN-α) in those cells. Here we show that Opn deficiency substantially reduced Toll-like receptor 9 (TLR9)-dependent IFN-α responses but spared expression of transcription factor NF-κB-dependent proinflammatory cytokines. Shortly after TLR9 engagement, colocalization of Opn-i and the adaptor molecule MyD88 was associated with induction of transcription factor IRF7-dependent IFN-α gene expression, whereas deficient expression of Opn-i was associated with defective nuclear translocation of IRF7 in pDCs. The importance of the Opn-IFN-α pathway was emphasized by its essential involvement in crosspresentation in vitro and in anti-herpes simplex virus 1 IFN-α response in vivo. The finding that Opn-i selectively coupled TLR9 signaling to expression of IFN-α but not to that of other proinflammatory cytokines provides new molecular insight into the biology of pDCs.Increasing evidence that innate immune responses can determine both the type and intensity of adaptive immune responses has stimulated great interest in the underlying regulatory mechanisms. The recognition phase of innate responses depends on a series of patternrecognition receptors, including Toll-like receptors (TLRs) expressed by dendritic cells (DCs), which detect a wide range of pathogen-associated molecules carried by bacteria and viruses 1 . Engagement of the TLR9 family of endosomal receptors by microbe-derived DNA triggers the production of large amounts of interferons α and β (IFN-αβ) 2 , key mediators that regulate the development of both innate and adaptive immunity [3][4][5][6] . However, the pathway initiated by TLR9 engagement that culminates in IFN-αβ production is not fully understood.

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

“…The OPN-siRNA was introduced into the animal with a hydrostatic pressure-mediated technique, hydrodynamic delivery (Liu et al 1999). OPN is thought to function not only in soluble form (OPN-s) as a cytokine but also in intracellular form, OPN-i (Shinohara et al 2006;Cantor and Shinohara 2009). Although anti-OPN Ab can only be accessible to and block OPN-s, OPN-siRNA may block both forms by reducing the expression in both compartments.…”

“…Second, the specific form of OPN, intracellular OPN, could induce IFN- secretion from plasmacytoid dendritic cells (pDC) in the presence of CpG in TLR9-MyD88-and IRF7-dependent manner (Shinohara et al 2006). IFN- also favors Th1-deviation.…”

“…OPN is widely produced by a variety of inflammatory cells, including T cells, macrophages, NK cells, and NKT cells Diao et al 2004;Diao et al 2008) and induces interleukin-12 (IL-12) and IFN- production and inhibits IL-10 expression (Ashkar et al 2000). Moreover, the intracellular isoform, OPN-i is now considered to promote the Th1 5 response through type I interferon production (Shinohara et al 2006, Cantor andShinohara 2009). OPN has therefore been considered to act as a cytokine contributing to the development of Th1-mediated immunity and diseases and is anticipated to be a therapeutic target for controlling these diseases.…”

Osteopontin: Role in immune regulation and stress responses

“…Recent findings have revealed that iOPN also mediates IFN-α expression in plasmacytoid dendritic cells by selectively coupling TLR9 signaling to expression of IFN-α (Shinohara et al, 2006).This indicates that intracellular and secreted OPN may differentially regulate signaling pathways in different cell lineage to influence the type and intensity of immune responses.…”

Plasma Osteopontin Modulates Chronic Restraint Stress-Induced Thymus Atrophy by Regulating Stress Hormones: Inhibition by an Anti-Osteopontin Monoclonal Antibody

“…M. Shinohara and H. Cantor (Dana Farber Cancer Institute, Boston, MA) (16). The breeding pairs were homozygous OPN Ϫ/Ϫ mice with 15 generations of backcrossing to the BALB/c background therefore considered 99.99% pure BALB/c background.…”