Dectin-2–induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis
Chie Miyabe, … , Tamihiro Kawakami, Andrew D. Luster
Chie Miyabe, … , Tamihiro Kawakami, Andrew D. Luster
Published June 6, 2019
Citation Information: J Clin Invest. 2019;129(9):3610-3624. https://doi.org/10.1172/JCI123778.
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Research Article Immunology Inflammation

Dectin-2–induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis

Abstract

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of CCR2+ inflammatory monocytes (iMos) into the aortic root and coronary arteries. iMos differentiated into monocyte-derived dendritic cells (Mo-DCs) in the vessel wall and were induced to release IL-1β in a Dectin-2/Syk/NLRP3 inflammasome–dependent pathway. IL-1β then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2–mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis.

Authors

Chie Miyabe, Yoshishige Miyabe, Laura Bricio-Moreno, Jeffrey Lian, Rod A. Rahimi, Noriko N. Miura, Naohito Ohno, Yoichiro Iwakura, Tamihiro Kawakami, Andrew D. Luster

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Figure 7

Dectin-2–dependent production of IL-1β from CD11c+ cells is required for CAWS-induced vasculitis.

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Dectin-2–dependent production of IL-1β from CD11c+ cells is required for...
(A) Heart tissue from WT mice was harvested 28 days after initial CAWS injection and assessed for cytokine expression by qPCR (n = 4–5 per group, mean ± SEM). (B) Vasculitis scores of IL1a–/– IL1b–/– mice or WT mice 28 days after CAWS injection (mean ± SEM, *P < 0.0001 versus WT). (C) Schematic of BMC mice generation using WT and IL1a–/– IL1b–/– mice. (D) Vasculitis scores were assessed 28 days after CAWS injection into 8-week-reconstituted WT → WT, WT → IL1–/– IL1b–/–, IL1a–/– IL1b–/– → IL1a–/– IL1b–/–, and IL1a–/– IL1b–/– → WT BMC mice (mean ± SEM, *P < 0.01 versus WT → WT). (E) Kinetics of IL-1β+ (DsRed+) cell numbers of the indicated immune cell subset per mg of heart tissue determined by flow cytometric analysis on day 0, 1, 2, 4, 7, 14, or 28 after CAWS injection of pIl1-DsRed mice (mean ± SEM, n = 3 per time point). (F) Dectin-2–/– or WT mice were injected with CAWS and 7 or 28 day later hearts were harvested and assessed for IL-1β expression by qPCR (mean ± SEM, n = 4–5 per group). (G) CD11cΔSyk mice or control mice were injected with CAWS and 7 or 28 day later hearts were harvested and assessed for IL-1β expression by qPCR (F and G; mean ± SEM, *P < 0.05, **P < 0.001 versus Sykfl/fl). P values were calculated using unpaired 2-tailed Student’s t test (B, F, and G) or 1-way ANOVA with Dunnett’s post hoc test (D).