Netrin-1 guides inflammatory cell migration to control mucosal immune responses during intestinal inflammation

Abstract

The intestinal epithelium is a dynamic barrier playing an active role in intestinal homeostasis and inflammation. Intestinal barrier function is dysregulated during inflammatory bowel disease (IBD), with epithelial cells playing a significant part in generating an inflammatory milieu through the release of signals that attract leukocytes to the intestinal lamina propria. However, it is increasingly appreciated that the intestinal epithelium mediates a counterbalancing response to drive resolution. Drawing analogies with neuronal development, where the balance of chemoattractive and chemorepellent signals is key to directed neuronal movement it has been postulated that such secreted cues play a role in leukocyte migration. Netrin-1 is one of the best-described neuronal guidance molecules, which has been shown to play a significant role in directed migration of leukocytes. Prior to our study the potential role of netrin-1 in IBD was poorly characterized. We defined netrin-1 as an intestinal epithelial-derived protein capable of limiting neutrophil recruitment to attenuate acute colitis. Our study highlights that the intestinal epithelium releases factors during acute inflammation that are responsible for fine-tuning the immune response. Exploration of these epithelial-mediated protective mechanisms will shed light on the complexity of the intestinal epithelial barrier in health and disease.

Keywords: apoptosis; inflammatory bowel disease; intestinal epithelial cells; leukocyte migration; neuronal guidance molecule.

Figure 1. Balance between chemoattraction and repulsion mediated by epithelial cells during intestinal inflammation. The chemokines known to regulate neutrophil (PMN) migration into the intestinal lamina propria during colitis are well established. Our findings in an acute murine model of colitis present the neuronal guidance molecule netrin-1 as a chemorepulsive factor released by intestinal epithelial cells that limits PMN recruitment to the inflamed intestine. Initial studies point to netrin-1 signaling through the A2B adenosine receptor (Adora2b) as the mechanism by which netrin-1 mediates its therapeutic effects. Adora2b signaling can induce intracellular signaling molecules that have been demonstrated to alter PMN migration. Our study reveals that the intestinal epithelium can also be a source of chemorepulsive cues during acute colitis.