New finding of ECM1 on M1 macrophage polarization in inflammatory bowel disease

Inflammatory Bowel Disease (IBD) is a refractory inflammatory disease, which mainly includes ulcerative colitis(UC) and Crohn’s disease(CD). Current studies suggest that IBD is a complex autoinflammatory disease determined by genetic and environmental factors as well as major cause of gastrointestinal cancer. Because of its complexity and refractory, the detailed pathogenesis and effective therapy of IBD has been the focus of research.

Recently, a work entitled“ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation” revealed new mechanism of inflammatory bowel disease and to provide therapeutic targets for clinical trial. The study was published online in PNAS ( Proceedings of the National Academy of Sciences of the United States of America ) on January 20, 2020 by team of Bing Sun from the Center for Excellence in Molecular and Cellular Science, Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), in collaboration with Prof. Jie Liu from Department of Digestive Diseases, Huashan Hospital, Fudan University.Among the identified IBD susceptibility genes(NOD2, IL-23 et al), extracellular matrix protein-1 (ECM1) was found to be strongly related to UC in 2008 . Since 2011, several works from Sun’s laboratory have reported the disease-related functions of ECM1 in Th2, Th17 and Tfh cells. However, no available evidence suggests the direct function of ECM1 in IBD.

In this work, by analyzing the samples of patients with ulcerative colitis and DSS-induced IBD mice model, researchers found that ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. Further study showed that ECM1 could regulate M1 macrophage polarization through GM-CSF/ STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. These results revealed a function of the IBD susceptibility gene ECM1 in colitis and the possible existence of the GM-CSF/STAT5 regulatory axis in macrophages and indicate that the attenuation of ECM1 function in macrophages is a potential strategy for IBD therapy.

Yaguang Zhang , Xuezhen Li, Zhongguang Luo and their colleagues from team led by Prof. Bing Sun and Jie Liu completed this work. This work was financially supported by the National Natural Science Foundation of China , the Ministry of Science and Technology of China and the Strategic Priority Research Program of the Chinese Academy of  Sciences.