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Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
Jia He, … , Lihua Lai, Qingqing Wang
Jia He, … , Lihua Lai, Qingqing Wang
Published June 27, 2019
Citation Information: J Clin Invest. 2019;129(9):3877-3893. https://doi.org/10.1172/JCI123374.
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Research Article Immunology Inflammation

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

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Abstract

Resident and inflammatory mononuclear phagocytes (MPhs) with functional plasticity in the intestine are critically involved in the pathology of inflammatory bowel diseases (IBDs), the mechanism of which remains incompletely understood. In the present study, we found that increased expression of the E3 ligase F-box and WD repeat domain–containing 7 (FBXW) in the inflamed intestine was significantly correlated with IBD severity in both human diseases and in mouse models. Myeloid Fbxw7 deficiency protected mice from colitis induced by dextran sodium sulfate (DSS) or 2,6,4-trinitrobenzene sulfonic acid (TNBS). Fbxw7 deficiency resulted in decreased production of the chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced the accumulation of CX3CR1int proinflammatory MPhs in colitis-affected colon tissue. Mice that received adeno-associated virus–shFbxw7 (AAV-shFbxw7) showed significantly improved survival rates and alleviation of colitis. Mechanism screening demonstrated that FBXW7 suppressed H3K27me3 modification and promoted Ccl2 and Ccl7 expression via degradation of the histone-lysine N-methyltransferase enhancer of zeste homolog 2 (EZH2) in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2 and Ccl7 in CX3CR1hi macrophages, thereby promoting the recruitment of CX3CR1int proinflammatory MPhs into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for the treatment of intestinal inflammation.

Authors

Jia He, Yinjing Song, Gaopeng Li, Peng Xiao, Yang Liu, Yue Xue, Qian Cao, Xintao Tu, Ting Pan, Zhinong Jiang, Xuetao Cao, Lihua Lai, Qingqing Wang

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Figure 8

EZH2 inhibits macrophage Ccl2 and Ccl7 expression through H3K27me3 modification.

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EZH2 inhibits macrophage Ccl2 and Ccl7 expression through H3K27me3 modif...
(A) Ezh2 in BMDMs was silenced with control siRNA (siNC) or Ezh2-specific siRNA (siEzh2) for 48 hours. The effects of siEzh2 on Ezh2 expression and H3K27me3 modification in BMDMs were analyzed by immunoblot. (B) The concentration of CCL2 and CCL7 in the culture medium of Fbxw7fl/fl and LysM+ Fbxw7fl/fl BMDMs after siEzh2 and LPS treatment was quantified by ELISA (n = 5). (C) GSK126 or DMSO (10 μM) was added to the cell culture medium for 2 days, and EZH2, H3K27me3, and H3 levels were detected by immunoblot assay. (D) The concentration of CCL2 and CCL7 in the culture medium of Fbxw7fl/fl and LysM+ Fbxw7fl/fl BMDMs after GSK126 and LPS treatment was quantified by ELISA (n = 5). (E) ChIP assay for enrichment of H3K27me3 on the promoters of Ccl2 and Ccl7 in BMDMs, followed by LPS treatment. Data are presented as the mean ± SD and are representative of at least 3 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test.
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