Accumulation of versican and lack of versikine ameliorate acute colitis

作者：Shamima Islam, Nushrat Jahan, Shahida Arbee, Sivasundaram Karnan, Hideto Watanabe · 发表于：Matrix Biology · 年份：2022 · DOI：10.1016/j.matbio.2022.02.004 · 被引用次数：14 · 研究领域：Proteoglycans and glycosaminoglycans research、Protease and Inhibitor Mechanisms、NF-κB Signaling Pathways

Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan that plays a key role in the formation of the provisional matrix. Here, we generated dextran sulfate sodium-induced colitis in knockin-mice, R/R, expressing ADAMTS-resistant versican, and investigated the impact of accumulating versican and its turnover in the inflammatory colon mucosa. Histologically, R/R colon showed decreased levels of tissue destruction and an increased number of myofibroblasts and macrophages. Characterization of inflammatory cells revealed an increase in F4/80+ macrophages in R/R colon, compared with wildtype, without a clear shift between M1 and M2 populations. Intestinal stroma exhibited a higher number of myofibroblasts in R/R, suggesting increased levels of tissue regeneration. Coculture of macrophages and stromal fibroblasts obtained from inflammatory colon showed that wild-type macrophages inhibited myofibroblastic differentiation of R/R fibroblasts but not wild-type. This inhibitory effect was due to an increased level of versikine, a cleaved fragment of versican by ADAMTS proteinases. Taken together, our results demonstrate versikine as the direct regulator that inhibits repair of inflamed tissue.