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 1

CAWS induces inflammatory monocyte recruitment into the heart on day 1.

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CAWS induces inflammatory monocyte recruitment into the heart on day 1. ...
(A) Representative H&E–stained horizontal section of the aortic root area from WT naive mice or on day 28 after 5 daily i.p. injections of CAWS beginning on day 0. Low-power field shows aortic root area and high-power field shows the ostium of the coronary artery within the aortic root. Scale bars: 400 μm (low-power images) and 100 μm (high-power images). (B and C) Coronal section isolated from naive or CAWS-injected WT mice (on day 1, 7, or 28) stained with anti-Ly6G/Ly6C (B) or anti-F4/80 (C) for IHC. Cropped high-power-field images show aortic root (upper panel) or myocardium (lower panel). Scale bars: 1 mm (low-power images) and 100 μm (high-power images). (D) Representative FACS analysis of cardiac neutrophil, macrophage, DC, and monocyte subsets recovered from CAWS-injected mice on day 1 after the first CAWS injection. One representative of 3 independent experiments. (E) Kinetics of absolute cell numbers of the indicated immune cell subset per mg of heart isolated during the course of CAWS-induced vasculitis (mean ± SEM, n = 4–5 mice per time point, *P < 0.05, **P < 0.01 versus day 0, using unpaired 2-tailed Student’s t test). (F) Schematic protocol for parabiosis experiment. (G) Tissue chimerism was analyzed in parabiotic pairs by measuring the frequency of host-derived leukocytes (CD45.1+) and partner-derived leukocytes (CD45.2+) on day 14 after CAWS injection (mean ± SEM, n = 4 mice). NS indicates statistically identical in the indicated organs among host-derived cells or partner-derived cells using ordinary 1-way ANOVA with Tukey’s post hoc test. (H) Representative FACS plots of each myeloid cell subset in the parabiotic mouse hearts on day 14 after the first CAWS injection. (I) Quantitation of chimerism for the indicated myeloid cell subsets (mean ± SEM, n = 4 mice). All values were statistically identical in indicated cell subsets among host-derived cells or partner-derived cells using ordinary 1-way ANOVA with Tukey’s post hoc test. cDC, cardiac DC.