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- Title
Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease.
- Authors
Masayoshi Ohkuro; Jun-Dal Kim; Yoshikazu Kuboi; Yuki Hayashi; Hayase Mizukami; Hiroko Kobayashi-Kuramochi; Kenzo Muramoto; Manabu Shirato; Fumiko Michikawa-Tanaka; Jun Moriya; Teruya Kozaki; Kazuma Takase; Kenichi Chiba; Agarwala, Kishan Lal; Takayuki Kimura; Makoto Kotake; Tetsuya Kawahara; Naoki Yoneda; Shinsuke Hirota; Hiroshi Azuma
- Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.
- Subjects
INFLAMMATORY bowel diseases; CROHN'S disease; CALRETICULIN; ULCERATIVE colitis; INTEGRINS; PATHOLOGY; SMALL molecules
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04420-4