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 September 3, 2019; First 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 8

CAWS activates the NLRP3 inflammasome and promotes IL-1β production via Dectin-2.

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CAWS activates the NLRP3 inflammasome and promotes IL-1β production via ...
(A) Representative immunofluorescent staining showing NF-κB p65 (red) nuclear translocation in WT and Dectin-2–/– BMDMs stimulated for 60 minutes with CAWS (10 μg/mL) or LPS (1 μg/mL). Cell nuclei were detected by DAPI (blue). Similar results are obtained from 3 independent experiments. Scale bars: 20 μm. (B) Quantitation of NF-κB p65 nuclear translocation in the indicated groups. Results are expressed as the percentage of cells with NF-κB p65–positive nuclei versus total cells. Similar results were obtained from 3 independent experiments (mean ± SEM, n = 3 per group, *P < 0.01 versus WT). (C) Vasculitis scores of WT, Aim2–/–, NLRP3–/–, or Caspase-1–/– mice on day 28 after CAWS injection (mean ± SEM, n = 4–8 mice per group, *P < 0.0001 versus WT). (D) H&E–stained sections of aortic root lesions isolated from Aim2–/–, NLRP3–/–, or Caspase-1–/– mice on day 28. Scale bars: 400 μm. (E) BMDCs from WT, Aim2–/–, NLRP3–/–, or Caspase-1–/– mice were stimulated with CAWS with or without inflammasome stimulators (LPS and MUCs) for 18 hours, and IL-1β release was assessed by ELISA (mean ± SEM, n = 3 per group, *P < 0.0001 versus WT). (F) BMDCs from Dectin-1–/–, Dectin-2–/–, or Card9–/– mice were stimulated with CAWS with or without inflammasome stimulators (LPS and MUC) for 18 hours, and IL-1β release was assessed by ELISA (mean ± SEM, n = 3–4 per group, *P < 0.0001 versus WT). P values were calculated using unpaired 2-tailed Student’s t test (B) or 1-way ANOVA with Dunnett’s post hoc test (C, E, and F).