New strategies to control dendritic cell activity

IDENTIFICATION OF THE NATURAL LIGAND FOR CLEC4C TO EVALUATE ITS ROLE ON THE RELEASE OF IFN-I BY PLASMACYTOID DENDRITIC CELLS. Plasmacytoid dendritic cells (pDC) are specialized in the production of interferon-I (IFN-I), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of IFN-I secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. IFN-I production is modulated by several receptors, including C-type lectin domain family 4, member C (CLEC4C). The natural ligand of CLEC4C is unknown. To identify it, here we probed a glycan array with a soluble form of the CLEC4C ectodomain. We found that CLEC4C recognizes complex type sugars with terminal galactose. Importantly, soluble CLEC4C bound peripheral blood leukocytes and tumor cells that express glycans with galactose residues at the non-reducing ends. The positive and negative modulation of galactose residues on cell membranes was paralleled by the regulation of IFN-I secretion by plasmacytoid dendritic cells in co-culture experiments in vitro. These results suggest that the modulation in the expression of non-sialylated oligosaccharides by invading pathogens or transformed cells may affect IFN-I response and immune surveillance. EFFECT OF PHOSPHODIESTERASE 4 INHIBITORS ON PLASMACYTOID DENDRITIC CELLS AND DENDRITIC CELLS. Dendritic Cells (DC) link innate and adaptive immunity and play a unique role in the presentation of antigens to naïve T cells. Moreover, upon activation, DC are able to induce Th1/Th2/Th17 polarization. Indeed, activation, migration, immunogenic and tolerogenic activities of DC are orchestrated by the release of cytokines by the local microenviroment. Deregulation of cytokine production is known to be involved in the breakdown of tolerance. Systemic Lupus Erythematosus (SLE), for example, is characterized by an aberrant production of IFN-I, abundantly secreted by immunocomplex-activated pDC. In early psoriatic lesions, instead, the anti microbial peptide LL-37, when bound to selfDNA, leads to an increased release of IFNα by pDC. Elevated levels of IFNα trigger myeloid DC activation that will better present self antigens to T cells and promote the expansion of autoreactive Th1/Th17 clones. Recently phosphodiesterase inhibitors (PDEi) were reported as an effective strategy to regulate cytokine production. Phosphodiesterases (PDEs) are unique enzymes metabolizing cAMP, a pivotal second messenger able to regulate inflammation and cytokine production. Phosphodiesterase 4 (PDE4) is one of the most studied since it is highly expressed by immune cells, endothelial cells and keratinocytes. The present work describes the results of a detailed in vitro analysis of the effect of PDE4-1, a new, low molecular weight inhibitor for PDE4 on several key aspects of the psoriasis pathogenetic model. We show that PDE4-1 efficiently reduce the secretion of IFN-I by activated plasmacytoid dendritic cells. On the other hand, when administered to in-vitro derived myeloid dendritic cells, this drug also inhibit the release of IL-12p70, an important Th1-driving cytokine, and of TNFα, IL-6 and IL-23, that are of fundamental importance for Th17 polarization, in addition to reducing the release of the Th1-attracting chemokine CXCL10/IP10. In summary, we demonstrate that PDE4-1 reduce the release of key pathogenetic mediators, involved in the current model of psoriasis.