A Path To Taming Inflammatory Macrophages

Scientists have identified a protein signaling pathway that is key to the generation of macrophages responsible for causing inflammatory bowel disease.

AsianScientist (Apr. 3, 2018) – Researchers at the Tokyo Medical and Dental University (TMDU), Japan, have discovered how dysregulated immune cells cause inflammation in the colon, a precursor to inflammatory bowel disease (IBD). Their work has been published in Mucosal Immunology.

The intestine encounters more foreign substances and potential toxins than other parts of the body, so it is not surprising that a healthy gut is maintained by the tight control of immune responses. Immune cells in the gut protect against harmful pathogens but tolerate harmless bacteria. However, an inappropriate immune response can lead to chronic inflammation and the development of IBD.

Macrophages are white blood cells that engulf pathogens and scavenge dying cells. They arise from the differentiation of precursor cells known as monocytes. However, the mechanisms underlying this differentiation in the gut, as well as how macrophages acquire properties to induce inflammation of the colon, were unclear.

In this study, a research group led by Dr. Yusuke Nakanishi of TMDU identified a signaling pathway involving the proteins IFNγ and Stat1 that is responsible for promoting inflammation in the gut.

“Mice lacking Stat1 expression differentiated fewer inflammatory macrophages from their monocyte lineage, and additionally developed less severe inflammation of their colons than control mice,” said Nakanishi. This suggested that Stat1 was required for an inflamed state to occur.

The researchers also demonstrated that the IFNγ-Stat1 axis enhanced access to the promoters of genes encoding inflammatory mediators, thus increasing the production of pro-inflammatory molecules. In addition, the team found that IFNγ signaling was required to maintain the macrophage population in the inflamed colon.

“We already knew that the response to pathogenic bacteria in the gut involves remodeling of the DNA-protein package known as chromatin, enabling access for the expression of genes involved in inflammation,” said corresponding author Professor Toshiaki Ohteki of TMDU. “This led us to investigate the role of IFNγ in a similar context, and we found that IFNγ loosened the chromatin structure around the promoters of two genes encoding inflammatory mediators, leading to an increase in their expression.”

This new understanding of how dysregulated macrophages develop in the colon during inflammation may lead to the identification of novel targets for IBD therapy, the researchers said.

The article can be found at: Nakanishi et al. (2018) IFN-γ-dependent Epigenetic Regulation Instructs Colitogenic Monocyte/macrophage Lineage Differentiation in vivo.


Source: Tokyo Medical and Dental University; Photo: Shutterstock.
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