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

Male 0301 basic medicine Colon Neutrophils Science Anti-Inflammatory Agents Mice, SCID Article Piperazines Jurkat Cells Mice 03 medical and health sciences Cyclohexanes Animals Humans Mice, Inbred BALB C 0303 health sciences Q Dextran Sulfate Healthy Volunteers 3. Good health Disease Models, Animal Neutrophil Infiltration Colitis, Ulcerative Female Calreticulin Integrin alpha Chains
DOI: 10.1038/s41467-018-04420-4 Publication Date: 2018-05-11T15:11:27Z
ABSTRACT
AbstractInflammatory 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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