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

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, 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 and Akiyoshi Fukamizu ()
Additional contact information
Masayoshi Ohkuro: University of Tsukuba
Jun-Dal Kim: University of Tsukuba
Yoshikazu Kuboi: Eisai Co., Ltd.
Yuki Hayashi: University of Tsukuba
Hayase Mizukami: University of Tsukuba
Hiroko Kobayashi-Kuramochi: Eisai Co., Ltd.
Kenzo Muramoto: Eisai Co., Ltd.
Manabu Shirato: Eisai Co., Ltd.
Fumiko Michikawa-Tanaka: Eisai Co., Ltd.
Jun Moriya: Eisai Co., Ltd.
Teruya Kozaki: Eisai Co., Ltd.
Kazuma Takase: Eisai Co., Ltd.
Kenichi Chiba: Eisai Co., Ltd.
Kishan Lal Agarwala: Eisai Co., Ltd.
Takayuki Kimura: Eisai Co., Ltd.
Makoto Kotake: Eisai Co., Ltd.
Tetsuya Kawahara: Eisai Co., Ltd.
Naoki Yoneda: Eisai Co., Ltd.
Shinsuke Hirota: Eisai Co., Ltd.
Hiroshi Azuma: Eisai Co., Ltd.
Nobuko Ozasa-Komura: Eisai Co., Ltd.
Yoshiaki Ohashi: Eisai Co., Ltd.
Masafumi Muratani: University of Tsukuba
Keiji Kimura: University of Tsukuba
Ieharu Hishinuma: Eisai Co., Ltd.
Akiyoshi Fukamizu: University of Tsukuba

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-04420-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04420-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-04420-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().