Department of Molecular Biotechnology and Health Sciences

Dendritic cells (DCs) are a heterogeneous group of professional antigen-presenting cells functioning as sentinels of the immune system and playing a key role in the initiation and amplification of innate and adaptive immune responses. DC development and functions are acquired during a complex differentiation and maturation process influenced by several factors
present in the local milieu. A common feature at pathologic sites is represented by hypoxia, a condition of low pO2, which creates a unique microenvironment affecting cell phenotype and behavior. Recently we investigated the impact of hypoxia on the generation of human mature DCs (mDCs). We identified by gene expression profiling a significant cluster of genes coding for immune-related cell surface receptors strongly up-regulated by hypoxia in monocyte-derived mDCs and characterized one of such receptors, TREM-1, as a new hypoxia-inducible gene in mDCs.
TREM-1 associated with DAP12 in hypoxic mDCs, and its engagement elicited DAP12-linked signaling, resulting in ERK-1, Akt, and IκBα phosphorylation and proinflammatory cytokine and chemokine secretion. We provided the first evidence that TREM-1 is expressed on mDCs infiltrating the inflamed hypoxic joints of children affected by juvenile idiopathic arthritis, representing a new in vivo marker of hypoxic mDCs endowed with proinflammatory properties.
In this project we will carry out studies aimed to characterize the role of hypoxia on functional behaviour of  DCs that populate the epidermis, known as Langerhans cells (LCs).  The skin is equipped with a high sophisticated system of immune surveillance that relies on a rich network of LCs in  the epidermis and DCs in the dermis.
The accomplishment of this research program will clarify the role of chronic hypoxia (1% of O₂) on:

the differentiation of LCs from human monocytes cultured with GM-CSF + IL-4 + TGF-b and TNF-α

• the ability of hypoxic LCs to induce proliferation of allogeneic T cells
• the gene expression profile of immunoregulatory receptors among which  TREM-1
• the ability of TREM-1 triggering on the induction of a pro-inflammatory phenotype of hypoxic LCs
•  the involvement of hypoxic LCs in some skin diseases characterized by hypoxia