Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice

• Published in: Free radical biology & medicine Vol. 134; pp. 153 - 164
• Main Authors: Takagi, Tomohisa, Homma, Takujiro, Fujii, Junichi, Shirasawa, Nobuyuki, Yoriki, Hiroyuki, Hotta, Yuma, Higashimura, Yasuki, Mizushima, Katsura, Hirai, Yasuko, Katada, Kazuhiro, Uchiyama, Kazuhiko, Naito, Yuji, Itoh, Yoshito
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019
• Subjects: Animals; Colitis - etiology; Colitis - metabolism; Colitis - pathology; Cytokines - metabolism; Dextran Sulfate - toxicity; Dextran sulfate sodium (DSS)-induced colitis; Endoplasmic Reticulum Stress; Female; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxiredoxin 4 (PRDX4); Peroxiredoxins - physiology; PBS; SDS; TBS; DSS; HRP; TBST; DAI; ER; MPO; GPX; ERO1; Endoplasmic reticulum stress; BSA; PRDX; PDI; UPR; ROS; iNOS; Peroxiredoxin 4 (PRDX4); FITC-dextran; WT; Dextran sulfate sodium (DSS)-induced colitis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.12.024

Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4-/y) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model. Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4-/y male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues. PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4-/y mice were significantly higher compared to those of WT mice. Specifically, PRDX4-/y mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4-/y compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4-/y compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4-/y compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4-/y than WT mice, which was consistent with severe ER stress under PRDX4 deficiency. Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4-/y than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation. [Display omitted] •ER-retained peroxiredoxin 4 (PRDX4) protein is highly expressed in the colon.•PRDX4 localizes to colonic epithelial cells.•PRDX4-/y mice show high disease severity of colitis.•The oxidative damage and ER stress are higher in PRDX4-/y than WT mice.•PRDX4 may represent a novel therapeutic molecule in intestinal inflammation.