CORDIS - Forschungsergebnisse der EU
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Immune mechanisms of osteopontin-mediated protection in allergic airway disease

Final Report Summary - OPN-IMMUNOREGULATION (Immune mechanisms of osteopontin-mediated protection in allergic airway disease)

Osteopontin (Opn) was known to promote effector responses facilitating a pro-inflammatory environment, especially of Th1- and Th17-associated autoimmunity. Our team had found that Opn could regulate allergic Th2 responses. However, the exact regulatory components involved were unknown. In addition, even though Opn is constitutively expressed, its role in non-inflammatory conditions remained elusive. With this proposal we aimed at understanding the mechanisms by which Opn affects regulatory components (tolerance) or inflammation depending on the setting. The project has proceeded as planned and we have achieved the main goals. Our results provide new insight into the biology of Opn, as well as into pathways implicated in the treatment of immune-mediated diseases.
We describe a novel pathway initiated by integrin activation and leading to IFN-beta induction in plasmacytoid dendritic cells (pDCs). This pathway has nothing to do with the usual TLR triggers (danger signals) that induce Type I IFN in pDCs, during either infection or inflammatory conditions. Just a fragment of osteopontin (Opn) - a protein constitutively expressed by several cells - triggers integrin alpha 4, activating a TLR-independent pathway resulting in Type I IFN expression in pDCs that uptake antigen. This process renders pDCs tolerogenic. Also, the same fragment of Opn drives pDC development. Our findings reveal an unexpected role for Opn in tolerance and, moreover, introduce the idea that integrin activation can act as “low level” danger signal important for tolerance maintenance, and possibly for setting cells ready to release high levels of Type I IFN when pathogens evade. In addition, we find that Opn drives T regulatory cells to an enhanced suppressive state both in vitro and in vivo, as they are able to control allergic airway inflammation and autoimmunity. Certain molecular pathways involved have been identified.
In inflammatory settings with TLR involvement, we find that a specific Opn fragment is responsible for enhancement of pathogenic Th17-mediated responses. We demonstrate that disrupting the interaction of this Opn domain with a different integrin (alpha 9), overexpressed on inflammatory DCs, suppresses the pathogenicity of these cells in vitro and in vivo. These results add unique insight into the biology of inflammatory DCs and their function during inflammation. Furthermore, we find that Opn directly and differentially affects recruitment and proliferation both of T central memory and effector allergic Th2 cells in lymph nodes. As Opn is involved in different inflammatory settings, it would be interesting to follow its effects on these cellular populations especially in vaccination.
Our genomic studies in the context of this project lead to identification of new molecular targets. Thus, we have important novel findings concerning the role of TIGIT in Th2 immunity and of certain steroid receptors in Th17 and Th2 biology and associated disease.
Overall, the project explored new questions in the field of cellular immunology, related to the function of osteopontin, during different settings. The outcomes lead to enhancement of our understanding of certain cellular responses during inflammation and tolerance maintenance, opening questions and strategies for future therapeutic approaches.