Protein gp96 Essential for Normal Inflammatory Response in the Gut, Study Finds

Protein gp96 Essential for Normal Inflammatory Response in the Gut, Study Finds

Researchers at the Medical University of South Carolina (MUSC) found that a protein called gp96 is necessary for normal function and balance of the resident immune cells in the gut, helping them distinguish between dangerous and normal microbes. The findings indicate the relevance of the protein in the maintenance of gut health and prevention of inflammation.

This finding was described in an article titled “Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c+ cells,” and featured in Scientific Reports.

“This study shines a light on the pathogenesis of inflammatory bowel disease and offers a positive impact on its future clinical management,” Bei Liu, MD, associate professor in the MUSC Department of Microbiology and Immunology, said in a press release.

The right balance between inflammatory and tolerant immune T-cells is essential for a healthy gut. In colitis, increased numbers of inflammatory immune T-cells, or more active ones, make these cells identify food elements or normal gut bacteria as dangerous components that must be destroyed.

This process of identification by immune T-cells in the gut is mediated by the activity of other immune cells called professional antigen-presenting cells (pAPCs). These pAPCs are responsible for detecting what is foreign or potentially harmful, and what belongs and is tolerable, and pass that information to immature T-cells for future correct recognition.

The research team led by Liu found that gut pAPCs that lacked a protein called gp96 would not be able to reach immature T-cells and pass important information, meaning that mature T-cells would not know what should be tolerated.

Researchers used a mice model genetically generated not to express the gp96 protein in their gut pAPCs and found that, due to this change in pAPCs dynamics, the number of inflammatory T-cells outnumbered tolerant ones.

This imbalance led the animals to develop inflammatory bowel disease. The animals lacking gp96 initially presented a normal growth rate. However, after 24 weeks, about 70 percent of the animals developed spontaneous colitis, whereas none of the normal gp96-expressing animals did. The gp96 knockout mice also had higher levels of a marker associated with chronic inflammation called immunoglobulin A (IgA).

“In summary, our study for the first time demonstrated that CD11c+ [pAPCs] cell-intrinsic gp96 is essential for maintaining gut tolerance and prevention of colitis,” the authors wrote.

More studies are required to understand the greater role of gp96 in inflammatory bowel diseases development in human patients, and its potential role on inflammation-associated colon cancer.