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| Osteopontin: Interfering with interferon
Osteopontin expression is required for interferon-α production in plasmacytoid dendritic cells. Plasmacytoid dendritic cells (pDCs) are innate immune system cells that release type I interferon (INF-α, INF-ß, INF-ω and INF-λ) upon viral infection. Toll-like receptors 7 (TLR7) and 9 (TLR9) regulate interferon transcription and protein secretion in pDCs. Previously, Osteopontin (Opn) expression was only known to be associated with functions such as bone resorption, and ventricular remodeling. However, a study in Nature Immunology by Shinohara et al. reveals that the phosphoprotein is also a key mediator of TLR9-dependent pDC interferon response in mice.
Binding of CpG oligonucleotides by TLR9 mimics microbial DNA binding in pDCs, thus triggering interferon production. While TLR9 is expressed in both pDCs and conventional DCs (cDCs), upregulation of Opn gene expression is only seen in pDCs after CpG-dependent ligation. The transcription factor T-bet is an essential component of T helper type 1 (TH1) lineage commitment and is known to regulate Opn expression in T cells. The authors show T-bet is also required for Opn expression in pDCs upon induction by CpG. Furthermore, they show that IFN-α expression in response to CpG is dramatically reduced in both Opn and T-bet-deficient pDCs, even though other proinflammatory cytokines were expressed normally. Although Opn has a signal peptide, the uncleaved precursor protein (Opn-i) remains intracellular. The authors show that in transfected Hek293 cells, Opn-i co-immunoprecipitates with Myd88 and the Tlr9 complex. Opn also co-localizes with these components in pDCs after TLR stimulation. Reconstitution of pDCs, but not cDCs, with signal peptide-mutated Opn resulted in increased IFN-α production. While Opn deficiency abolishes IFN-α responses, it does not affect the expression of other inflammatory cytokines. In Opn-deficient DCs the transcription factor IRF7 fails to translocate to the nucleus, while overexpression of Opn in HEK293 cells causes a MyD88 and IRF7-dependent transcriptional response. This indicates that Opn is an integral member of the TLR9-MyD88-IRF7 pathway, which is essential for interferon type I production. The Opn-IFN-α pathway has a role in cross-presentation by heterogeneous DCs after TLR9 engagement in vitro and heterogeneous antigen presenting cells in vivo. Opn-deficient mice, when challenged with inactivated HSV-1, exhibit severely reduced INF-α production. This study sheds light on interferon production in pDCs and reveals how intracellular Opn is functionally distinct from secreted Opn. Whether clarification of the molecular regulation of interferon production will yield future therapeutic targets remains to be determined. Clare Garvey References
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