The hypoxic environment induces a migratory or a proinflammatory phenotype in DCs depending on their maturation stage. Identification of TREM-1 as a common hypoxia marker

Purpose/Objective: DCs are central to the orchestration of innate/adaptive immunity and maintainance of self-tolerance. DC functions are acquired during a complex differentiation and maturation process tightly regulated by signals present in the microenvironment, and deregulated DC responses may result in amplification of inflammation, loss of tolerance, or establishment of immune escape mechanisms. Pathological conditions are characterized by low partial oxygen pressure (pO2, hypoxia). Understanding DC biology in low O2 environment may open new therapeutic opportunities for inflammation and cancer. Materials and methods: We defined the hypoxic transcriptome of immature (i) and mature (m) DCs generated from human monocytes under chronic hypoxic conditions (5 days, 1% O2). Results: We present data showing that chronic hypoxia differentially reprograms DCs depending on their maturation stage. Specifically, hypoxia promotes the onset of a migratory phenotype in iDCs through the upregulation of chemokine receptors and an inflammatory state in mDCs by increasing production of proinflammatory, Th1-priming chemokines/cytokines. Interestingly, hypoxia induces profound changes in the expression of a significant cluster of genes coding for immunoregulatory receptors in both cell subsets. Among them, we identified the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig receptor family and a strong amplifier of inflammation, as a hypoxia-inducible gene in both iDCs and mDCs in vitro and confirmed TREM-1 expression in vivo in DCs infiltrating the inflamed hypoxic joints of Juvenile Idiopathic Arthritis patients. TREM-1 inducibility by hypoxia was reversed by cell reoxygenation and mediated by HIF-1a. TREM-1 engagement elicited DAP12-linked signaling resulting in the production of proinflammatory cytokines/ chemokines and upregulation of T cell costimulatory molecules and chemokine homing receptors. Conclusions: These findings indicate that reduced O2 availability critically contributes to the persistence and amplification of inflammation by regulating iDC migration and mDC capacity to promote leukocyte trafficking in diseased tissues and identify TREM-1 as a novel marker of hypoxic DCs endowed with pro-inflammatory properties. The potential implications of DC reprogramming by hypoxia for disease progression will be discussed.