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THU0107 Hypoxia-Inducible Factor 2A is Preferentially Expressed by M2-Like Synovial Macrophages in Rheumatoid Arthritis
  1. W. J. Hardy1,
  2. S. Aynsley1,
  3. U. Fearon2,
  4. D. Veale2,
  5. A. G. Wilson1,
  6. M. Muthana1
  1. 1Academic Unit of Rheumatology, University of Sheffield, Sheffield, United Kingdom
  2. 2UK & Translation Rheumatology Research Group, Dublin, Ireland

Abstract

Background In rheumatoid arthritis (RA), the influx of inflammatory cells as well as the aggressive proliferation of fibroblast-like synovial cells (FLS) outstrips the oxygen supply from blood vessels leading to joint hypoxia. Macrophages accumulate in hypoxic disease sites including RA joints where they possess broad pro-inflammatory, destructive and remodelling potential leading to inflammation and joint destruction. Macrophages respond to hypoxia by up regulating the hypoxia inducible transcription factors– HIF-1 and -2, which leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism.

Objectives The objective of our study was to characterise the HIF-1 and HIF-2 expressing macrophage populations in response to joint hypoxia, and in particular to dissect out the effects of HIF-2 in a murine model of arthritis.

Methods Arthroscopy sections (5 microns) from RA patients with mild (~40mmHg), moderate (~15mmHg) & severe (~3mmHg) joint hypoxia were immunostained with anti-HIF 1 and 2 and co-localised with the pan-macrophage marker CD68 as well as other macrophage markers. Murine arthritis using K/BxN serum transfer was induced in 10 – 12 week old mice bearing a targeted deletion of HIF-2 in myeloid cells (HIF2fl/fl; LysM-Cre+’ mice) or control mice (HIF2fl/fl; LysM-Cre-). Mice were given 100ul injections of serum on day 0 and 2 and inflammation was monitored daily.

Results In patients with mildly hypoxic joints, macrophages expressed HIF-1+ and CD147 and were found in small clusters localised to the lining layer. Macrophages in patients with severely hypoxic joints predominately expressed HIF-2+ and the VEGF receptor Flt-1. These macrophages also expressed the angiopoietin receptor ‘Tie2’ and the mannose receptor ‘CD206’ both associated with M2-like macrophages. The significance of HIF-2 was evaluated in a murine arthritis model where macrophages having a genetic deletion of HIF-2 developed less severe arthritis compared to control mice.

Conclusions HIF-2+ macrophages expressing M2-like markers were predominantly expressed in patients with severely hypoxic joints and loss of HIF-2 expression by macrophages in a mouse model of arthritis prevented disease development. Taken together, these findings suggest that HIF-2 is the major hypoxia-inducible transcription factor in synovial macrophages and targeting HIF-2 is likely to be an effective therapeutic strategy.

Disclosure of Interest None Declared

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