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Important role of CCR2 in a murine model of coronary vasculitis
Hernan G Martinez1, Marlon P Quinones, Fabio Jimenez
1Department of Medicine (MC 7870), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Insights
Genetic inactivation of chemokine receptor (CCR) 2 protects against vasculitis by modulating T and B cell responses and maintaining immune balance. This finding offers potential new therapeutic targets for Kawasaki disease (KD).
Area of Science:
- Immunology
- Vascular Biology
- Infectious Disease
Background:
- Chemokines and receptors are implicated in innate immunity and Th17/Treg cell imbalance in Kawasaki disease (KD) pathogenesis.
- The role of chemokine receptor (CCR) 2 in vasculitis, particularly in KD, requires further elucidation.
Purpose of the Study:
- To investigate the protective role of CCR2 genetic inactivation against vasculitis.
- To elucidate the mechanisms by which CCR2 influences immune cell dynamics and inflammatory responses in a model of vasculitis.
Main Methods:
- Induction of experimental vasculitis using Candida albicans water-soluble cell wall extracts (CAWS).
- Genetic inactivation of CCR2 in mice (Ccr2(+/+) vs. Ccr2(-/-)).
- Analysis of immune cell populations (T cells, B cells, monocytes), cytokine production (IL-6), and immune cell trafficking.
Main Results:
- Genetic inactivation of CCR2 conferred protection against aortic and coronary vasculitis induced by CAWS.
- Both T and B cells were essential for vasculitis induction, with CCR2 modulating their roles.
- CAWS induced CCR2-dependent inflammatory monocyte mobilization and IL-6 production, leading to Treg depletion and Th17 expansion, which were ameliorated in CCR2-deficient mice.
Conclusions:
- CCR2 plays a significant role in the pathogenesis of vasculitis, as demonstrated in this KD model.
- Targeting CCR2 presents a potential therapeutic strategy for vasculitis, especially in treatment-resistant cases.
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.