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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 7

FBXW7 mediates the ubiquitination of EZH2 in macrophages.

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FBXW7 mediates the ubiquitination of EZH2 in macrophages.
(A) Immunoblot...
(A) Immunoblot analysis of EZH2 expression in BMDMs treated or not with MG132 for 8 hours and stimulated with LPS for the indicated durations. (B) Immunoblot analysis of EZH2 in lysates of Fbxw7fl/fl and LysM+ Fbxw7fl/fl BMDMs treated with CHX (40 μg/mL) for the indicated durations after stimulation with LPS for 1 hour. (C) Quantification of relative EZH2 protein levels. (D) Immunoblot analysis of HEK293T cells cotransfected for 36 hours with Myc-FBXW7 plus Flag-EZH2, HA-Ub, and GFP vectors treated or not with MG132. (E) Immunoblot analysis of HEK293T cells cotransfected for 36 hours with Myc-FBXW7, HA-Ub, and GFP, along with a vector for Flag-EZH2 and Flag-EZHh2 (261, 265, 367, and 371A, 4A). (F) Immunoblot analysis of the ubiquitination of EZH2 in HEK293T cells cotransfected with Flag-EZH2, HA-Ub, and increasing concentrations (wedge) of vectors for the Myc-FBXW7 constructs, and treated with MG132 for 6 hours before cell harvesting. (G) Immunoblot analysis of the ubiquitination of EZH2 in HEK293T cells cotransfected with Flag-EZH2, Myc-FBXW7, HA-Ub, the mutant ubiquitin HA-R48 Ub, or HA-R63 Ub, and treated with MG132 before cell harvesting. (H) Immunoblot analysis of the K48 ubiquitination of EZH2 in Fbxw7fl/fl and LysM+ Fbxw7fl/fl BMDMs stimulated with LPS. Data are representative of at least 3 independent experiments.

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