ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2875

Macrophage Expression of Hypoxia-Inducible Factor-2 Alpha Promotes Rheumatoid Arthritis Progression

Munitta Muthana1,2, William Jacob Hardy3, Sarah Hawtree1, Fiona Wright1, Ursula Fearon4, DJ Veale5, Mauro Perretti6 and Anthony G. Wilson7, 1Infection and Immunity, University of Sheffield, Sheffield, United Kingdom, 2Medical School, University of Sheffield, Sheffield, United Kingdom, 3University of Sheffield, Sheffield, United Kingdom, 4Dublin Academic Medical Centre, Translational Rheumatology Research Group, Dublin, Ireland, 5Consultant Rheumatologist, St. Vincent’s University Hospital, Dublin, Ireland, 6Biochemical Pharmaology, Barts and the London School of Medicine, London, United Kingdom, 7University College Dublin, Dublin, Ireland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis II

Session Type: Abstract Submissions (ACR)

Background/Purpose

Hypoxia exists in many diseased tissues including arthritic joints, atherosclerotic plaques and malignant tumours. Macrophages accumulate in these hypoxic sites 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.

The purpose of our study was to characterise the 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 from RA patients with mild (~40mmHg) or severe (~3mmHg) joint hypoxia were immunostained with anti-HIF 2 and co-localised with the pan-macrophage marker CD68 as well as other M1 and M2 macrophage markers. Cell-specific RNA was purified from CD68+ve macrophages in RA tissue by laser capture microdissection (LCM) and differential gene expression was determined using the RT2 Profiler PCR inflammatory arrays. The significance of HIF-2 was also evaluated in the K/BxN serum transfer model in mice bearing a targeted deletion of HIF-2 in myeloid cells including macrophages (HIF2fl/fl; LysM-Cre+’ mice). Arthritis was assessed clinically and histologically.

Results

In patients with severely hypoxic joints macrophages predominately expressed HIF-2 as well receptors for VEGF (Flt1), angiopoietin ‘Tie2’ and mannose ‘CD206’ markers associated with M2-skewed macrophages. However, expression of CXCL-2, -4, -5, IL-1a, IL-6 IL-8 & TNFa were also all up regulated compared to macrophages from mildly hypoxic joints. In vivo, macrophages lacking HIF2 significantly suppressed disease development indicating an indispensable role for HIF2 in supporting macrophages in K/BxN serum-transfer arthritis.

Conclusion

HIF-2 expressing macrophages have an M1 & M2-like phenotype in patients with severely hypoxic joints and loss of HIF-2 in macrophages suppressed arthritis in mice. Collectively, our data identify HIF-2 as an important regulator of macrophage function, suggesting it may be a useful therapeutic target for treating RA.

Disclosure:

M. Muthana,
None;

W. J. Hardy,
None;

S. Hawtree,
None;

F. Wright,
None;

U. Fearon,
None;

D. Veale,
None;

M. Perretti,
None;

A. G. Wilson,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-expression-of-hypoxia-inducible-factor-2-alpha-promotes-rheumatoid-arthritis-progression/