EMBRACING SLANDC

"Exploring the Molecular Bases that Regulate Apoptosis, Cytokine production and Interaction with Neutrophil Granulocytes by 6-sulfo LacNAc+ dendritic cells (slanDC)"

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 Obiettivo del progetto (Objective)

'Dendritic cells (DC) are composed of multiple subsets with distinct functions at the interface of the innate and adaptive immunity. Two major subsets of DC circulate in human peripheral blood: the myeloid DC (mDC) and the plasmacytoid DC (pDC), which can be distinguished by the expression of specific surface markers. Within mDC, slanDC are the most abundant in human blood and are characterized by a selective phenotype (6-sulfo LacNAc, CD1c–, CD11c, CD14–, CD16, CD45RA, C5aR). They undergo spontaneous maturation if cultured in the absence of erythrocytes. Once matured, they are characterized by a high potential to produce pro-inflammatory cytokines such as IL-12p70 and TNFα, to prime naive T cells to become Th1 cells and to activate NK cell responses. While slanDCs may certainly play a crucial role in the control of immune response, a detailed knowledge on their involvement in autoimmunity, transplantation rejection and cancer biology is still missing. The central importance of slanDC in immune regulation makes, therefore, additional studies necessary to better understand the biologic role of this DC subset. For such a purpose, the project will focus on three main objectives: (1) to study the molecular mechanism(s) regulating IL-12p70 production by slanDC during their maturation and their cross-talk with neutrophils. To reach this objective, I will determine how IL-12p70 gene expression is controlled at a transcriptional and post-transcriptional level upon activation by TLR agonists and other stimuli. (2) to investigate the molecular mechanism(s) whereby LPS regulates slanDC survival: expression of Bcl-2 family proteins and ceramide metabolism will be analyzed. (3) to study the pattern of chemokine/chemokine receptor expression by TLR-activated slanDC. Results obtained from this project will provide new knowledge on the functional specializations of human DC subsets and, therefore, new concepts to immune disease pathogenesis and design of novel therapies.'

Introduzione (Teaser)

Manipulation of the immune system to tackle diseases requires a deep understanding of its biology. In this context, European researchers studied a newly identified population of immune cells and how it functions within the immune system.

Descrizione progetto (Article)

Dendritic cells (DCs) are antigen-presenting cells of the immune system that play an important role in innate and adaptive immunity. Late in the 1990s, researchers identified a subpopulation of dermal myeloid DCs with distinct phenotype, which they named 6-sulfo LacNAc+ dendritic cells (slanDCs).

SlanDCs secrete large amounts of pro-inflammatory cytokines such as TNF? and IL-12, and are implicated in the pathophysiology of numerous diseases including Crohn's disease and rheumatoid arthritis. Their undisputed role in regulating immune responses necessitates the detailed investigation of their biology. With this in mind, the EU-funded EMBRACING SLANDC project set out to study the mechanisms implicated in the maturation, migration and survival of these cells.

Scientists characterised surface marker expression on activated slanDCs and preliminarily showed that epigenetic mechanisms may regulate IL12 expression in these cells. To understand how lipopolysaccharide negatively affects slanDC survival, they looked at senescence mechanisms involving extracellular signals, autocrine/paracrine effects by endogenous cytokines and death receptor expression. Observations suggested that slanDC death could be induced, in part, through a reactive oxygen species-mediated oxidative process.

With respect to their role in disease, scientists looked at the co-localisation of slanDCs with other immune cells and investigated their migratory properties. In this context, emphasis was given to the expression of chemokine receptors and the capacity of the cells to chemoattract neutrophils.

The results obtained from this project provided new knowledge on the functional specialisation of human slanDCs. Project outcomes offer new concepts on disease pathogenesis that could help in designing novel therapies for various immune diseases.