Important role of CCR2 in a murine model of coronary vasculitis.

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.

CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B.

We postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.

MMP-Activated Fluorescence Imaging Detects Early Joint Inflammation in Collagen-Antibody-Induced Arthritis in CC-Chemokine Receptor-2-Null Mice, In-Vivo.

The Standard measures of experimental arthritis fail to detect, visualize, and quantify early inflammation and disease activity. Here, we describe the use of an injectable MMP-activated fluorescence agent for in vivo quantification of acute inflammation produced by collagen-antibody-induced arthritis (CAIA) in CC chemokine receptor-2 (Ccr2(-/-)) null mice. Although Ccr2(-/-) DBA1/J mice were highly susceptible to and rapidly developed CAIA, the standard clinical assessment of fore or hind paw thicknesses was unable to detect significant acute inflammatory changes (days 3-10). Remarkably, noninvasive, in situ, MMP-activatable fluorescent imaging of Ccr2(-/-) DBA1/J mice with CAIA displayed acute joint pathology in advance of clinically measurable acute inflammation (days 5, 7, and 10). These results were confirmed by the histology of ankle joints, which showed significant inflammation, bone loss, and synovial hyperplasia, compared to control mice at postimmunization day 5. The MMP-mediated fluorescence technique holds tremendous implications for quantifiable examination of arthritis disease activity of acute joint inflammation.