Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo

• Published in: Blood 2011-03, Vol.117 (9), p.2625-2639
• Main Authors: Bosco, Maria Carla, Pierobon, Daniele, Blengio, Fabiola, Raggi, Federica, Vanni, Cristina, Gattorno, Marco, Eva, Alessandra, Novelli, Francesco, Cappello, Paola, Giovarelli, Mirella, Varesio, Luigi
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Antigen-presenting cells; Arthritis; Arthritis, Juvenile - genetics; Arthritis, Juvenile - pathology; Biological and medical sciences; Biomarkers - metabolism; Blood; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell surface; Chemokines; Chemokines - metabolism; Children; Cross-Linking Reagents - pharmacology; Cytokines; DAP12 protein; Data Mining; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Differentiation; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Hypoxia; Immune system; Immunoregulation; Inflammation; Inflammation Mediators - metabolism; Joint diseases; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - metabolism; Microenvironments; Monocytes; Monocytes - cytology; Oxygen - pharmacology; Phenotype; Phosphorylation; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Synovial Fluid - drug effects; Synovial Fluid - metabolism; Triggering Receptor Expressed on Myeloid Cells-1
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-06-292136

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. Little is known about the impact of hypoxia on the generation of mature DCs (mDCs). In this study, 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. Finally, 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.