The hypoxic microenvironment modulates monocytic and dendritic cell inflammatory gene expression (133.10)

Abstract

Abstract Hypoxia is a condition of low oxygen tension occurring in inflammatory lesions which creates a special microenvironment conditioning cell physiology. We investigated the molecular bases underlying the immunoregulatory functions of monocytes (Mn) and of terminally differentiated dendritic cells (mDCs) within the hypoxic microenvironment both in vitro and in vivo. Mn and mDCs hypoxic transcriptome was assessed using high-density oligonucleotide microarrays. The molecular pathways underlying gene transcription regulation by hypoxia were evaluated by promoter-driven reporter studies and EMSA. Profound modulation of the gene expression pattern was detected following Mn and DC exposure to 1% O2. We identified a significant cluster of hypoxia-responsive genes with immunological relevance, among which the macrophage inflammatory protein-3α (MIP-3α/CCL20) and the cytokine/extracellular matrix protein, osteopontin (OPN). Hypoxic upregulation of both genes was confirmed in vitro in primary Mn, Mn-derived macrophages, and DCs and in vivo in Mn cell recruited to the synovial joints of patients affected by Juvenile Idiopatic Arthritis (JIA), and associated with hypoxia-inducible factor-1α (HIF-1α) expression and NF-kB transcriptional activation. These studies lead to new perspectives on the impact of hypoxia on mononuclear phagocyte functions and to the definition of the mechanisms linking low pO2 to the pathogenesis of chronic inflammation.