Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease

• DOI: 10.1038/s41467-018-04420-4
• Publication Date: 2018-05-11T15:11:27Z
• Authors: Masayoshi Ohkuro; Jun-Dal Kim; Yoshikazu Kuboi; Yuki Hayashi; Hayase Mizukami; Hiroko Kobayashi-...; Kenzo Muramoto; Manabu Shirato; Fumiko Michikawa-...; Jun Moriya; Teruya Kozaki; Kazuma Takase; Kenichi Chiba; Kishan Lal Agarwala; Takayuki Kimura; Makoto Kotake; Tetsuya Kawahara; Naoki Yoneda; Shinsuke Hirota; Hiroshi Azuma; Nobuko Ozasa-Komura; Yoshiaki Ohashi; Masafumi Muratani; Keiji Kimura; Ieharu Hishinuma; Akiyoshi Fukamizu
• Keywords: Pathogenesis

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), calcium-binding chaperone, known as partner in activation of integrin α subunits (ITGAs). The relationship between their interaction pathogenesis IBD largely unknown. Here we show that small molecule, orally active ER-464195-01, inhibits CRT binding ITGAs, which suppresses adhesiveness both T cells neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced mice reveals increased expression pro-inflammatory genes downregulated ER-464195-01. Its prophylactic therapeutic administration mouse models ameliorates severity diseases. We propose leukocytes infiltration via ITGAs necessary for onset development inhibition this may be novel strategy treatment IBD.