Sentinel Genes and Epigenetics of Injury

Recent research has identified the existence of sentinel factors on circulating inflammatory cells that monitor and maintain homeostatic equilibrium in normal tissues. A sentinel gene is defined as being: a) membrane anchored on the cell surface; b) expressed on circulating leukocytes of healthy volunteers; c) have an activation mechanism dependent on proteolytic processing. Disrupted by injury, the scope of their altered expression pre-defines the intensity of the injury response and hence forecasts injury recovery. We have recently identified a novel role for the gene c2orf40, which codes for the protein Ecrg4, in the injury response. We have demonstrated in animal models and clinical samples that Ecrg4 is expressed on the surface of leukocytes, shed from the cell surface after injury, and chemotactic for macrophages (J Leukocyte Biology. 2012;91:773-81). Our focus is on determining whether sentinel gene expression can forecast clinical outcomes and predict infectious complications during the recovery after burn injury.

While animal models generally focus on inbred strains for studies of injury and inflammation, patient populations are diverse with many confounding variables that are often not easily understood with standard genetic approaches. Epigenetic modification modulating gene expression is emerging as an important area of research to better understand the plasticity of the genome and the capacity for environmental variables to influence gene expression. As a strategy that complements VNS as a 'physiologic intervention' to regulate set point, epigenetics is a 'genetic set point' that we predict influences not only gene expression but also outcomes of injury which has been recently demonstrated in CNS injury. For example, recent progress in the characterization of epigenetic modifications in peripheral blood cells set point might explain individual differences in the inflammatory response to injury. Epigenetic status can be altered through several mechanisms including DNA methylation, histone modifications, and through regulatory RNAs. The environment, including dietary modifications, can affect these epigenetic changes. Indeed, diet has been shown to alter DNA methylation patterns on specific genes within human peripheral blood mononuclear cells (PBMCs) suggesting that an individual's environmental exposures could affect their inflammatory set-point and alter their response to injury.