title: 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.
abstract: 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 pO(2), 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.
authors.affiliation: Laboratory of Molecular Biology, G. Gaslini Institute, Genova, Italy. mariacarlabosco@ospedalegaslini.ge.it
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.forename: Daniele
authors.initials: D
authors.lastname: Pierobon
authors.forename: Fabiola
authors.initials: F
authors.lastname: Blengio
authors.forename: Federica
authors.initials: F
authors.lastname: Raggi
authors.forename: Cristina
authors.initials: C
authors.lastname: Vanni
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Alessandra
authors.initials: A
authors.lastname: Eva
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001171:Arthritis, Juvenile / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D057225:Data Mining; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D010100:Oxygen / Q000494:pharmacology; D010641:Phenotype; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D018925:Chemokines; D003432:Cross-Linking Reagents; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C110546:TYROBP protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D010100:Oxygen