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

Abstract

2E) and F4/80 + macrophages (Figure 2F) after DSS treatment for 5 days compared with expression in the colons of healthy mice. These results suggest that increased FBXW7 expression in monocytes and macrophages was correlated with local colonic inflammation in both humans and mice. Fbxw7 deficiency attenuates experimental colitis. To investigate the role of Fbxw7 in macrophages in colitis, LysM-Cre + Fbxw7 fl/fl (LysM + Fbxw7 fl/fl) mice and their control littermates (Fbxw7 fl/fl) were subjected to acute colitis induction using 3% DSS. Colitisinduced macroscopic changes (body weight loss, diarrhea, and rectal bleeding) were significantly alleviated in the LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Figure 3A). LysM + Fbxw7 fl/fl mice sacrificed on day 9 displayed significantly longer colons (Figure 3B), milder epithelial damage, and deceased areas of mucosal ulceration (Figure 3C and Supplemental Figure 2A) compared with Fbxw7 fl/fl littermates. Moreover, expression levels of the tight junction genes Cldn1, Cldn2, Ocln, and Tjp1 (Supplemental Figure 2B) and of TJP1 protein (Supplemental Figure 2C) were significantly higher in the epithelia of LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates after DSS treatment, which indicated that the epithelial barrier integrity was less disrupted in mice with myeloid-specific Fbxw7 deficiency. At the same time, LysM + Fbxw7 fl/fl mice showed significantly improved survival rates compared with Fbxw7 fl/fl littermates after 4% DSS treatment (Figure 3D), indicating that Fbxw7 deficiency protects mice from DSS-induced colitis. During the recovery period of intestinal inflammation, the rate of body weight gain was more rapid in LysM + Fbxw7 fl/fl mice than in Fbxw7 fl/fl littermates (Figure 3E). Moreover, LysM + Fbxw7 fl/fl mice had longer colon lengths than did their Fbxw7 fl/fl littermates (Figure 3F) on day 15. Similarly, TNBS-induced colon shortening, the disease activity index (DAI), body weight loss, and epithelial damage were also alleviated in LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Supplemental Figure 3, AD). These findings indicate that myeloid Fbxw7 deficiency attenuates experimental colitis. Fbxw7 deficiency decreases proinflammatory MPh accumulation. Microbiota-induced inflammation is critical for the regulation of intestinal homeostasis. To determine whether the decreased DSS colitis susceptibility in LysM + Fbxw7 fl/fl mice was mediated by shifts in gut microbiota, we analyzed the fecal microbiota composition in LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates. The relative abundance of bacteria at the phylum level and the species composition cluster according to operational taxonomic units (OTUs) among LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates are shown in Supplemental Figure 4A and Figure 4A, respectively. Moreover, microbial community diversity (Figure 4B) and microbial community composition (Supplemental Figure 4B) were not significantly different between LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl li...

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