The ADAMTS cleavage site in versican core protein is critical for versican turnover in the inflamed colon, as evidenced by higher levels of versican deposition in V1R homozygote mice (R/R), whose versican is resistant to ADAMTS cleavage.
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Under dextran sulfate sodium-induced acute colitis, the R/R colon showed decreased levels of tissue destruction and an increased number of myofibroblasts and macrophages.
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Athough HA deposition correlated with accumulated Vcan, R/R colon exhibited an expansive HA network in the submucosa of R/R colon, independent of Vcan deposition.
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To investigate the cross-talk between fibroblasts and macrophages, we established a co-culture system in which macrophages are plated on fibroblasts, separated by a 0.22 micron membrane.
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Under the co-culture system, wild-type macrophages inhibited myofibroblastic differentiation of R/R fibroblasts but not wild-type fibroblasts, suggesting that versikine produced by macrophages inhibits differentiation of fibroblasts toward myofibroblasts. Over-expressed versikine inhibited the differentiation.
Abstract
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.
