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
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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

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Figure 5

MMP3 contributes to IFX nonresponse by mediating its cleavage.

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MMP3 contributes to IFX nonresponse by mediating its cleavage. (A) Mice ...
(A) Mice given 2.5% DSS were treated with 2 mg/mL 4MU (in drinking water), 160 μg NNGH (i.p. injection, every other day), or a combination (n = 7/group). Body weight changes were monitored. (B) Colon length was measured on day 8. (C) Histological damage was evaluated by H&E staining. Original magnification, ×15; ×27 (insets). (D) The correlation between pretreatment mucosal MMP3 expression and posttreatment serum IFX concentration in patients with IBD was analyzed. (E) The structure of human IgG1 antibody and the cleavage sites of MMP3 in IFX, UST, and VDZ (left). IFX, UST, and VDZ were incubated with 10 μg/mL recombinant MMP3 for 24 hours, and the cleavage of antibodies was confirmed by immunoblotting (right). (F–H) Intestinal mucosa from patients with IBD was collected prior to VDZ treatment (VDZR, n = 10; VDZNR, n = 10), and MMP3 expression was evaluated by QPCR (F), ROC curve analysis showed the role of MMP3 expression in predicting VDZ responsiveness (G), and the correlation between mucosal levels of HAS2 and MMP3 was analyzed (H). *P < 0.05; **P < 0.01; ***P < 0.001. Unpaired, 2-tailed Student’s t test was used for F; ANOVA followed by Kruskal-Wallis test and Dunn’s correction was used for A–C; Spearman’s rank correlation test was used for D and H.