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

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 behaviour. Little is known about the impact of hypoxia on the generation of mature (m)DCs. In this study, we identified by gene expression profiling a significant cluster of genes coding for immune-related cell surface receptors strongly upregulated 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 pro-inflammatory 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 pro-inflammatory properties.