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

Nature Communications
Masayoshi OhkuroAkiyoshi Fukamizu

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.

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Citations

Jul 25, 2019·Frontiers in Chemistry·Monica BaiulaAlessandra Tolomelli
Aug 16, 2019·Rheumatology International·Asli Kirectepe AydinEda Tahir Turanli
Sep 18, 2020·International Journal of Molecular Sciences·Shuichi MatsudaYoshitoshi Kasuya
May 18, 2020·International Immunopharmacology·Tingting ZhangJie Wu
Oct 7, 2021·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Nicola J WyattChristopher A Lamb

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Datasets Mentioned

BETA
GSE83687
GSE98407
GSE109728

Methods Mentioned

BETA
proximity ligation assay
pull-down
PMA
surface plasmon resonance
NMR
RNA-seq
PCR
PCA
antisense oligonucleotides
electrophoresis

Software Mentioned

ToppGene Suite
Prism5
Duolink Image Tool
CLC Genomics Workbench
CLC Genomic Workbench
Biacore T100 BIAevaluation
GraphPad
Biacore
Flowjo

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