Important role of CCR2 in a murine model of coronary vasculitis

Abstract

BackgroundChemokines 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).ResultsHere 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.ConclusionCollectively, 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.

β-mannosyl linkages inhibit CAWS arteritis by negatively regulating dectin-2-dependent signaling in spleen and dendritic cells

“…Therefore, neutrophils play an important role in CAWS-vasculitis and exhibit the characteristics of neutrophils such as (i) prolonged survival in inflammatory tissue, (ii) the production of a variety of inflammatory and tissue mediators in blood vessels, such as reactive oxygen species, arachidonate metabolites, proteases and glycosidases, are strongly related to the degradation and remodeling of blood vessels 36,37 . Furthermore, we found that CCR2, a receptor for MCP-1, deficient mice were resistant to CAWS-vasculitis 10 . As MCP-1 is a chemotactic factor for macrophages, the local accumulation of macrophages plays an equally important role to that of neutrophils.…”

“…CAWS activated the lectin pathway of complement 8 , and was found to be a ligand for dectin-2 and the pattern recognition receptor (PRR) for pathogen-associated molecular patterns (PAMPs), having a C-type lectin structure 9 . Very recently, we and others have found that mice deficient in CCR2 and mice deficient in myeloperoxidase were resistant to CAWS-vasculitis 10,11 . In contrast to analyses for the molecular mechanisms of inflammation and immunity, the chemical structures required for CAWS-vasculitis have been limited.…”

Aetiological Significance of Infectious Stimuli in Kawasaki Disease

“…In a murine model of vasculitis, Candida albicans watersoluble fraction (CAWS) is used as the inducer. Marked inflammatory change is observed in the aortic root, including the coronary arteries in CAWS-treated mice (89,90). While CCR2 and GM-CSF play an indispensable role in its pathogenesis (89,90), T and B cells are also involved in the vasculitis (89).…”

Kawasaki disease: a matter of innate immunity

“…To date, two other animal models of KD coronary arteritis have been established. These mouse models showed that crude microbe‐associated molecular patterns (MAMPs)/PAMPs from Lactobacillus caseii and Candida albicans induce acute coronary vasculitis (Table ). Thus, these animal studies confirmed that stimulation of innate immunity with molecules such as NOD1 ligands induces vasculitis that mimics the coronary artery lesions of KD.…”