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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Calreticulin / antagonists & inhibitors
  • Calreticulin / immunology*
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / immunology*
  • Colon / cytology
  • Colon / immunology
  • Colon / pathology
  • Cyclohexanes / pharmacology*
  • Cyclohexanes / therapeutic use
  • Dextran Sulfate / toxicity
  • Disease Models, Animal
  • Female
  • Healthy Volunteers
  • Humans
  • Integrin alpha Chains / immunology*
  • Integrin alpha Chains / metabolism
  • Jurkat Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Neutrophil Infiltration / drug effects
  • Neutrophil Infiltration / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Protein Binding
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology


  • Anti-Inflammatory Agents
  • CALR protein, human
  • Calreticulin
  • Cyclohexanes
  • Integrin alpha Chains
  • Piperazines
  • Dextran Sulfate