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Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease
- Source :
- Nature Communications, Nature Communications, Vol 9, Iss 1, Pp 1-10 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
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.<br />Inflammatory bowel disease (IBD) is initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Here, the authors show that inhibition of the calreticulin binding to integrin α subunits ameliorates the severity of IBD in animal models.
- Subjects :
- Male
0301 basic medicine
Neutrophils
T-Lymphocytes
Anti-Inflammatory Agents
General Physics and Astronomy
Mice, SCID
Inflammatory bowel disease
Jurkat cells
Piperazines
Transcriptome
Pathogenesis
Jurkat Cells
Mice
0302 clinical medicine
lcsh:Science
Mice, Inbred BALB C
Multidisciplinary
biology
Dextran Sulfate
Ulcerative colitis
Healthy Volunteers
Neutrophil Infiltration
030220 oncology & carcinogenesis
Female
Integrin alpha Chains
Protein Binding
Colon
Science
Integrin
digestive system
Article
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Cyclohexanes
medicine
Animals
Humans
Colitis
business.industry
General Chemistry
medicine.disease
digestive system diseases
Disease Models, Animal
030104 developmental biology
Cancer research
biology.protein
lcsh:Q
Colitis, Ulcerative
Calreticulin
business
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....7826e9df2096ac62b95fd2e58e5ec81d