Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Evidence for CXCL16 As An Endothelial Progenitor Cell Chemotactic Factor.

Ruth1,  Jeffrey H., Isozaki1,  Takeo, Amin1,  M. Asif, Lesch1,  Charles A., Arbab2,  Ali S., Koch3,  Alisa E.

University of Michigan, Ann Arbor, MI
Henry Ford Hospital, Detroit, MI
Department of Veteran's Affairs and University of Michigan, Ann Arbor, MI

Background/Purpose:

We and others have previously shown that the transmembrane chemokine CXCL16 and its counterpart CXCR6 are important in the pathogenesis of rheumatoid arthritis (RA), predominantly via recruitment and stimulation of monocytes and T-cells. Here, we investigated the possibility that CXCR6 is expressed on human endothelial progenitor cells (EPCs), human dermal microvascular endothelial cells (HMVECs) and mouse lung endothelial cells (ECs). We also examined if CXCL16 recruits EPCs to developing neovasculature in rheumatoid arthritis (RA) synovium in vivo, and finally, if CXCR6 deficiency attenuates arthritis development and vascular formation in the K/BxN serum induced arthritis model.

Methods:

We utilized the RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera system to examine EPC recruitment into engrafted human synovium injected intragraft with RA synovial fluid (SF) immunodepleted of CXCL16 or sham depleted with non-specific IgG. In addition, CXCR6 deficient (CXCR6 -/-) and wild-type (Wt) C57BL/6 mice were primed to develop K/BxN serum induced arthritis and evaluated for joint swelling. Joint tissue homogenates from these mice were examined for hemoglobin (Hb) content as a measure of total joint tissue vascularity, whereas OCT embedded joint tissue was examined for vascular formation and leukocyte migration by immunofluorescence histology. Lastly, EC populations including HMVECs, human EPCs from human cord blood and primary mouse ECs from lung tissue were all examined for CXCR6 expression by immunofluorescence.

Results:

We show that CXCR6 is prominently expressed on the cell surface of human EPCs. CXCR6 is also expressed on HMVECs and mouse lung ECs and can be upregulated by interleuin-1b (IL-1b) or lipopolysaccharide (LPS) respectively. We also examined the recruitment of human EPCs in the RA ST SCID mouse chimera system and found that SCID mice injected intragraft with RA SF immunodepleted of CXCL16 showed a significant reduction in EPC recruitment compared to mice injected similarly with sham depleted RA SF. Finally, using the K/BxN serum induced inflammatory arthritis model, CXCR6-/- mice showed significantly reduced joint swelling compared to Wt mice at day 5 after serum induction. We measured Hb content in joint tissue homogenates from the K/BxN serum induced mice and discovered profound reductions in Hb levels, that correlated with reductions in monocyte and T-cell recruitment to arthritic joint tissue in CXCR6-/- compared to Wt mice. These findings indicate that CXCR6 deficiency reduces EPC migration to RA synovium, as well as vasculature formation and pro-inflammatory leukocyte recruitment in K/BxN serum induced arthritis.

Conclusion:

We show that CXCR6 is expressed on mouse and human ECs and can be upregulated by pro-inflammatory stimuli. We also show that EPCs migrate into RA synovium towards soluble CXCL16 in RA SF. Additionally, K/BxN mice lacking CXCR6 have a reduced arthritic phenotype including reductions in Hb content, vasculature and leukocyte infiltration into inflamed ST. These results indicate that CXCL16 and its receptor CXCR6 may be a central ligand-receptor pair for inducing EPC recruitment and vascular formation in RA synovium.

To cite this abstract, please use the following information:
Ruth, Jeffrey H., Isozaki, Takeo, Amin, M. Asif, Lesch, Charles A., Arbab, Ali S., Koch, Alisa E.; Evidence for CXCL16 As An Endothelial Progenitor Cell Chemotactic Factor. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :731
DOI:

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