Targeting hyaluronan synthesis enhances the therapeutic effectiveness of biologics in inflammatory bowel disease
Peng Xiao, Zhehang Chen, Xuechun Cai, Wenhao Xia, Xia Liu, Zhangfa Song, Huijuan Wang, Yuening Zhao, Youling Huang, Yu Zhang, Ke Guo, Haotian Chen, Rongbei Liu, Changcheng Meng, Yanfei Fang, Yunkun Lu, Qian Cao
Peng Xiao, Zhehang Chen, Xuechun Cai, Wenhao Xia, Xia Liu, Zhangfa Song, Huijuan Wang, Yuening Zhao, Youling Huang, Yu Zhang, Ke Guo, Haotian Chen, Rongbei Liu, Changcheng Meng, Yanfei Fang, Yunkun Lu, Qian Cao
View: Text | PDF
Research Article Gastroenterology Immunology

Targeting hyaluronan synthesis enhances the therapeutic effectiveness of biologics in inflammatory bowel disease

Abstract

Although biologics have been revolutionizing the treatment of inflammatory bowel diseases (IBD) over the past decade, a significant number of patients still fail to benefit from these drugs. Overcoming the nonresponse to biologics is one of the top challenges in IBD treatment. In this study, we revealed that hyaluronan (HA), an extracellular matrix (ECM) component in the gut, is associated with nonresponsiveness to infliximab and vedolizumab therapy in patients with IBD. In murine colitis models, inhibition of HA synthase 2–mediated (HAS2-mediated) HA synthesis sensitized the therapeutic response to infliximab. Mechanistically, HA induced the expression of MMP3 in colonic fibroblasts by activating STAT3 signaling, thereby mediating the proteolytic cleavage of multiple IgG1 biologics. Finally, we found that macrophage-derived factors upregulated HAS2 expression in fibroblasts, thereby contributing to infliximab nonresponse. In summary, we identified a pathogenic connection between abnormal ECM remodeling and biologics nonresponse and provided insights for the precise therapy for IBD.

Authors

Peng Xiao, Zhehang Chen, Xuechun Cai, Wenhao Xia, Xia Liu, Zhangfa Song, Huijuan Wang, Yuening Zhao, Youling Huang, Yu Zhang, Ke Guo, Haotian Chen, Rongbei Liu, Changcheng Meng, Yanfei Fang, Yunkun Lu, Qian Cao

×

Figure 6

Macrophages upregulate HAS2 expression in fibroblasts.

Options: View larger image (or click on image) Download as PowerPoint
Macrophages upregulate HAS2 expression in fibroblasts. (A and B) Mice we...
(A and B) Mice were given 2.5% DSS after macrophage depletion with clodronate liposomes (n = 6/group), and body weight changes were monitored (A) and histological damage was evaluated by H&E staining (B). Original magnification, ×15; ×27 (insets). (C) The expression of HAS2 and MMP3 in colon tissues was evaluated by QPCR on day 8 (n = 4–6/group). (D and E) HcFBs were treated with MSN or M+LPSSN for 24 hours, and the expression of HAS2 and MMP3 was evaluated by QPCR. (F) The infiltration of CD68+ macrophages was evaluated in the colonic mucosa of IFXR and IFXNR patients by immunofluorescence staining. Scale bar: 50 μm. (G) The levels of pretreatment mucosal CD68 expression were evaluated in IFXR and IFXNR patients with IBD by QPCR (IFXR, n = 20; IFXNR, n = 15). (H) ROC curve analysis indicated the role of mucosal CD68 expression in predicting IFX responsiveness. (I and J) The correlations between mucosal CD68 and HAS2 (I) or MMP3 (J) expression in IFX cohort were analyzed by Spearman’s rank correlation test. (K) The levels of pretreatment mucosal CD68 expression were evaluated in VDZR and VDZNR patients with IBD by QPCR (VDZR, n = 10; VDZNR, n = 10). (L) ROC curve analysis indicated the role of mucosal CD68 expression in predicting VDZ responsiveness. (M and N) The correlations between mucosal CD68 (M) and HAS2 (N) expression in the VDZ cohort was analyzed by Spearman’s rank correlation test. *P < 0.05; **P < 0.01; ***P < 0.001. Unpaired, 2-tailed Student’s t test was used for C–E, G, and K; ANOVA followed by Kruskal-Wallis test and Dunn’s correction was used for A and B; and Spearman’s rank correlation test was used for I, J, M, and N.