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Nat Commun. 2018 May 17;9(1):1982. doi: 10.1038/s41467-018-04420-4.

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

Author information

1
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
2
Research Institute, EA Pharma Co., Ltd., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-8681, Japan.
3
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.
4
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
5
Department of Genome Biology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
6
Genome Biology Core, Transborder Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
7
Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
8
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan. akif@tara.tsukuba.ac.jp.
9
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. akif@tara.tsukuba.ac.jp.

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.

PMID:
29773794
PMCID:
PMC5958137
DOI:
10.1038/s41467-018-04420-4
[Indexed for MEDLINE]
Free PMC Article

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