Abstract
The human genome is constantly exposed to exogenous and endogenous DNA damaging factors that frequently cause DNA damages. Unless repaired, damaged DNA can result in deleterious mutations capable of causing malignant transformation. Accordingly, cells have developed an advanced and effective surveillance system, the DNA damage response (DDR) pathway, which maintains genetic integrity. In addition to well-defined outcomes, such as cell cycle arrest, apoptosis, and senescence, another consequence of DDR activation is the induction of natural killer group 2 member D ligands (NKG2D-Ls) on the surface of stressed cells. Consequently, NKG2D-Ls-expressing cells are recognized and eliminated by NKG2D receptor-expressing immune cells, including NK cells, and various subsets of T-cells. Recent pieces of evidence indicate that commensal microbial imbalance (known as dysbiosis) can trigger DDR activation in host cells, which may result in sustained inflammatory responses. Therefore, dysbiosis can be seen as an important source of DNA damage agents that may be partially responsible for the overexpression of NKG2D-Ls on intestinal epithelial cells that is frequently observed in patients with inflammatory bowel disease and other disorders associated with altered human microbiota, including the development of colorectal cancer. In this article, we discuss recent evidence that appears to link an altered human microbiota with autoimmunity and carcinogenesis via the activation of DDR signals and the induction of NKG2D-Ls in stressed cells.
Highlights
The DNA damage response (DDR) is a highly efficient network of cellular pathways that play a crucial role in maintaining DNA integrity [1, 2]
Increased expression of natural killer group 2 member D (NKG2D)-Ls on the surface of intestinal epithelial cells and its recognition by NKG2D receptor-expressing immune cells is believed to contribute to the pathogenesis of inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn’s disease [33,34,35] and dysregulated gut microbiota has been etiologically linked to IBD and colorectal cancer (CRC) [27, 36, 37]
During the last few years, remarkable progress has been made in our understanding of the molecular mechanisms of DDR activation and its role in various cellular processes like aging and cancer development, and it has become apparent that the immune system constitutes an important component of the cellular response to DNA damage stressors [99]
Summary
Group 2 Member D Immune Receptor: From Dysbiosis to Autoimmunity and Carcinogenesis. Recent pieces of evidence indicate that commensal microbial imbalance (known as dysbiosis) can trigger DDR activation in host cells, which may result in sustained inflammatory responses. Dysbiosis can be seen as an important source of DNA damage agents that may be partially responsible for the overexpression of NKG2D-Ls on intestinal epithelial cells that is frequently observed in patients with inflammatory bowel disease and other disorders associated with altered human microbiota, including the development of colorectal cancer. We discuss recent evidence that appears to link an altered human microbiota with autoimmunity and carcinogenesis via the activation of DDR signals and the induction of NKG2D-Ls in stressed cells
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