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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 1

Increased FBXW7 expression in inflamed intestinal tissues in humans.

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Increased FBXW7 expression in inflamed intestinal tissues in humans.
(A)...
(A) Representative immunohistochemical staining of paraffin-embedded sections of colon specimens obtained from colonic biopsies from patients with UC or CD and healthy controls. Comparison of staining intensity (TissueGnostics) among the groups is shown. Original magnification, ×40. Scale bar: 50 μm. (B) Immunofluorescence staining for FBXW7 (red), CD68 (green), and DAPI for nuclei (blue) in healthy human tissue and CD tissue. Scale bars: 100 μm (whole colon section) and 50 μm (enlarged insets). Red arrows point to CD68+ macrophages with high expression of FBXW7. FBXW7 mRNA expression in peripheral blood monocytes (C) from healthy controls (n = 50) and from patients with IC (n = 22), UC (n = 24), or CD (n = 44), or in peripheral blood lymphocytes (D) from healthy controls (n = 30) and from patients with IC (n = 22), UC (n = 24), or CD (n = 33). *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Tukey’s multiple comparisons test. Data are presented as the mean ± SEM and are representative of 3 independent experiments.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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