Researchers from the Chinese Academy of Sciences and Huashan Hospital, Fudan University, demonstrate a new mechanism of inflammatory bowel disease (IBD) pathogenesis.
The study published online on PNAS in January 2020, Professor Sun Bing’s team form the Center for Excellence in Molecular and Cellular Science, Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with Professor Liu Jie form Huashan Hospital, Fudan University, demonstrated a novel mechanism involved in the pathogenesis of IBD and proposed therapeutic targets to be tested in clinical trials.
At present, studies have only shown that IBD is a complex autoinflammatory disease that results form genetic and environmental factors. It is also known to be a major cause of gastrointestinal cancer. Due to its complex and refractory nature, researchers have focused on understanding in detail the pathogenesis of IBD and finding and effective therapy.
IBD-susceptibility genes that were identified include extracellular matrix protein-1 (ECM-1) gene that was found to be strongly related to ulcerative colitis in 2008. Since 2011, Professor Sun’s laboratory has reported on the disease-related functions of ECM-1 gene in Th2, Th17 and Tfh cells. But no available data suggested that ECM-1 gene plays a direct role in IBD.
In the present study, the researchers analysed tissue samples from patients with ulcerative colitis and a DSS-induced IBD mice model.
From which they found that ECM-1 gene was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions. The ECM-1 gene expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM-1 gene resulted in an increase of arginase 1 (ARG1) gene expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment.
Further study showed that ECM1 protein could regulate M1 macrophage polarization through the GM-CSF/STAT5 signalling pathway. Pathological changes in mice with dextran sodium sulphate-induced IBD were alleviated by the specific knockout of the ECM-1 gene in macrophages.
These results reveal a role for the IBD-susceptibility gene ECM-1 in colitis and the possible existence of a GM-CSF/STAT5 regulatory axis in macrophages, indicating that the attenuation of ECM1 function in macrophages is a potential strategy for IBD therapy. [APBN]