Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation

Abstract

We previously reported that syndecan‐2 expression is increased on the colonic epithelium during chronic inflammation. Here, we report that syndecan‐2 exhibits a different pattern of site‐specific colonic expression during acute inflammation. Syndecan‐2 expression was up‐regulated predominantly in the proximal colon of dextran sulfate sodium‐induced colitis mice. The colitis‐associated up‐regulation of syndecan‐2 was barely detected in Rag‐1−/− (recombination activating gene 1 knockout) mice under colitis‐inducing conditions. Increased syndecan‐2 expression correlated with increased levels of infiltrated CD4+IL‐17A+ T cells in the proximal colon. Serum levels of IL‐17A were increased during the acute inflammatory response in normal mice but not Rag‐1−/− mice. IL‐17A directly induced IL‐17 receptor (IL‐17RA) and syndecan‐2 expression in ex vivo‐cultured proximal colon tissues and adenoma cell lines from proximal colon. IL‐17RA knockdown reduced the IL‐17A‐mediated syndecan‐2 expression in SNU1235 cells. No elevation of syndecan‐2 or IL‐17RA was observed in colonic tissues from IL‐17A−/− mice during colitis induction. Finally, increased expression of syndecan‐2 and IL‐17RA was observed in the proximal colons of cecal ligation and puncture‐induced sepsis mice and infectious pan colitis patients. Together, these data suggest that acute inflammation induces syndecan‐2 expression predominantly in the proximal colon via IL‐17A‐IL‐17RA signaling during the early stage of the inflammatory response and that proximal colonic syndecan‐2 might be a biomarker for acute inflammation.—Hong, H., Song, H.‐K., Hwang, E. S., Lee, A. R., Han, D. S., Kim, S.‐E., Oh, E.‐S. Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation. FASEB J. 33, 11381–11395 (2019). http://www.fasebj.org

Colocalization with MMP-7 in the Distal Colon is Crucial for Syndecan-2 Shedding in Dextran Sulfate Sodium-Induced Colitis Mice

“…To further investigate the direct role of MMP-7 in the extracellular shedding of syndecan-2 in colon tissues, we collected colonic tissues from acute DSS-induced mice and treated these tissues with MMP-7 in the absence or presence of an MMP inhibitor ( Figure 6 ). Consistent with a previous report, 24 we found that acute inflammation mediated by DSS induced expression of syndecan-2 predominantly in the proximal colon, but not detectable amounts of MMP-7 in the proximal colon ( Figure 6A ). The direct application of MMP-7 enzyme to ex vivo-cultured proximal colon tissues expressing syndecan-2 increased the levels of shed syndecan-2 in the tissue culture media, and this was inhibited by cotreatment with 500 nM MMP-7 inhibitors (GM6001) ( Figure 6B ), further confirming that MMP-7 mediates the extracellular domain shedding of syndecan-2 in colon tissues.…”

“… 21 We also recently reported evidence suggesting that syndecan-2 expression might be increased during the inflammatory response. 20 , 24 Here, we further investigated whether syndecan-2 shedding occurs during inflammation. First, acute inflammation on syndecan-2 shedding was assessed.…”

“… 23 These findings suggest that syndecan-2 may also regulate inflammatory responses. Interestingly, during acute inflammation, syndecan-2 expression was up-regulated predominantly in the proximal colon of colitis-induced mice, 24 suggesting that syndecan-2 plays site-specific functional roles in the colonic epithelium. Our group further showed that IL-1α induces syndecan-2 shedding in colorectal cancer cell lines, 25 and that shed syndecan-2 stimulates colorectal cancer activities.…”

Syndecans in Inflammation at a Glance

“…Both syndecan-1 and IL-17 are shown to be increased in nasal polyps, a chronic inflammation in the nasal cavity (48). Syndecan-2 expression is elevated in endothelial cells during inflammation, where they can directly bind with cytokines (e.g., CXCL-8) and induce the expression of other cytokines (e.g., IL-1α, IL-17A + ) (25,49). The silencing of syndecan-4 in HUVEC cells resulted in an elevation of pro-inflammatory factors (e.g., CXCL-8), which suggests that a loss of syndecan-4 may result in an aggravated inflammatory response.…”

Syndecans and Pancreatic Ductal Adenocarcinoma

“…In a recent study, the authors reported an upregulation of syndecan-2 in response to acute-induced inflammation in mice colons. This study also reports high expression levels of syndecan-2 in other inflammation-associated diseases, like colitis and sepsis, as this high-level expression is a good marker for acute inflammation and acute inflammation-associated diseases [87]. Another study using human umbilical vascular endothelial cells (HUVECs) demonstrated that syndecan-4 expression increased after inducing inflammation using lipopolysaccharides (LPS) and IL-1 (which together mimic a bacterial infection and a general inflammatory condition).…”