Recently, the team of Professor Zhu Shu of the University of Science and Technology of China has made new progress in intestinal immunity research, and has made a new interpretation of the function of Gasdermin-D (GSDMD) protein in food tolerance, providing a new direction for the treatment of food allergy. On June 15, the relevant research results were published in Cell.
Schematic diagram of GSDMD molecules responding to pathogens and food antigens in different cells. Photo courtesy of China University of Science and Technology
How the body’s immune system recognizes self-and non-self-antigens has always been a core question in immunology. The body has developed a central tolerance mechanism against self-antigens to prevent the immune system from attacking self-antigens (1960 Nobel Prize in Physiology or Medicine). For non-self-antigens, the immune system has developed systems that sense pathogenic signals and initiate immune activation and clearance mechanisms (2011 Nobel Prize in Physiology or Medicine), but for antigens that are harmless to the human body, such as antigens from commensal microorganisms or food in the intestine, the immune system chooses to induce peripheral tolerance mechanisms to avoid a strong immune response that endangers itself. Among them, the mechanism of how food antigens are recognized and initiate immune tolerance has been unclear.
GSDMD protein, as a key executive protein that mediates cell pyroptosis, has received extensive attention from scholars in the field in recent years. When cells are stimulated by pathogen-related molecular patterns and damage-related molecular patterns, the signaling receptors in the cells activate aspartate kinase family members 1/4/5/8/11 in a spartosome-dependent or non-dependent manner, and produce p30 fragments from the N-terminus cleavage of GSDMD, which in turn leads to cell pyrosis and inflammatory factor release by porous cell membrane. These functions are mainly found when explored in myeloid cells, and in the physiological state, GSDMD is widely expressed in a variety of tissues and organs, and as a member of the Gasdermin family, GSDMD is also highly expressed in the intestine, especially in the small intestine. Therefore, the non-pyrostotic function of GSDMD and what specific physiological roles it plays in the intestine have also become scientific questions that need to be explored.
In this work, the researchers first performed western blot detection on GSDMD in each tissue cell in physiological state, and found that among the tissue samples tested, only an shear band about 13,000 daltons the size of 13 thousand daltons could be detected in the epithelial cells of the anterior small intestine.
Further exploration revealed that this shear band comes from the N-terminus of GSDMD and is produced by food antigens activating CASPASE-3/7 in duodenal epithelial cells, thereby cleaving the 88-position aspartate of GSDMD. Through immunofluorescence staining and RNA sequencing, the researchers found that N13 fragments would enter the nucleus to induce the expression level of second-class molecules in anterior small intestinal epithelial cells. Through single-cell RNA sequencing and other means, the researchers found that the deletion of N13 fragments caused the decline of epithelial cell type II molecules, which further led to the decrease of Tr1 (type 1 regulatory T cells) cells. Since Tr1 cells are also thought to be one of the key cells for inducing food tolerance, the researchers speculate that N13 fragments will eventually be involved in inducing food tolerance. To this end, the researchers constructed two groups of food tolerance models for mice with a variety of gene expression backgrounds: peanut extract-induced peanut allergy model and chicken egg albumin-induced delayed hypersensitivity model, and finally confirmed that one of the physiological functions of GSDMD in the intestine is to participate in the construction of host food tolerance.
According to the researchers, the work elaborates that GSDMD in the anterior small intestine will form an N13 fragment under food induction, which enters the nucleus with the help of the nuclear pore complex, and assists in enhancing the transcriptional regulation of STAT1 on Ciita A (class II major histocompatibility complex transactivator), which increases the expression of the main histocompatibility complex class II molecules in small intestinal epithelial cells, thereby inducing the upregulation of Tr1, and ultimately promoting the formation of food tolerance. Provide new ideas for the treatment of food allergies. (Source: Wang Min, China Science News)
Related paper information:https://doi.org/10.1016/j.cell.2023.05.027