Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
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
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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Research Article Immunology Inflammation

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

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 3

LysM+Fbxw7fl/fl mice show attenuated experimental colitis.

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LysM+Fbxw7fl/fl mice show attenuated experimental colitis. Fbxw7fl/fl a...
Fbxw7fl/fl and LysM+ Fbxw7fl/fl mice were administered water or 3% DSS for 7 days to induce acute colitis, followed by a 2-day recovery period on normal drinking water. (A) Body weight changes, diarrhea, and rectal bleeding scores were assessed daily as described in Methods (n = 5). (B) Gross morphology of colons from Fbxw7fl/fl and LysM+ Fbxw7fl/fl mice. Colon lengths were measured on day 9 (n ≥ 5). (C) H&E-stained images of colon sections. Scale bars: 200 μm (whole colon section) and 50 μm (enlarged insets). (D) Fbxw7fl/fl and LysM+ Fbxw7fl/fl mice were administered 4% DSS to induce acute colitis. Survival of mice was monitored until day 15 (n = 10). ***P < 0.001, by log-rank test. (E) Body weight changes during intestinal inflammation and the recovery period (n = 5). (F) Length of colons from Fbxw7fl/fl and LysM+ Fbxw7fl/fl mice sacrificed after 7 days of 3% DSS treatment and 8 days’ recovery with drinking water (n = 5). Data are presented as the mean ± SEM and are representative of 3 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test (A, B, E, and F).