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Open Access Highly Accessed Research article

Important role of CCR2 in a murine model of coronary vasculitis

Hernan G Martinez12, Marlon P Quinones3, Fabio Jimenez12, Carlos Estrada1, Kassandra M Clark1, Kazuo Suzuki4, Noriko Miura5, Naohito Ohno5, Sunil K Ahuja26 and Seema S Ahuja1*

Author Affiliations

1 Department of Medicine (MC 7870), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

2 South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, 78229-3900, USA

3 Department Psychiatry, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, 78229-3900, USA

4 Inflammation Program, Department of Immunology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan

5 Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji Tokyo, 192-0392, Japan

6 The Veterans Administration Center for Aids and HIV-1 infection, South Texas Veterans Health Care System, San Antonio, TX, USA

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BMC Immunology 2012, 13:56  doi:10.1186/1471-2172-13-56

Published: 17 October 2012

Abstract

Background

Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD).

Results

Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2+/+ mice, processes that were ameliorated following the genetic inactivation of CCR2.

Conclusion

Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.

Keywords:
CCR2; Coronary vasculitis; Treg; Treg/Th17 imbalance