Neutrophils enlist IL-22 to restore order in the gut

Mammals are eukaryotic organisms, yet they can harbor up to hundreds of trillions of bacteria in their intestines through an elegant form of mutualism (1). To extract maximal benefit from these bacteria, the mucosal immune system must respond in a tolerogenic manner while remaining poised to vigorously react to potential pathogens (2). Thus, intestinal immune cells are charged with an exceedingly difficult task: to know when to remain tolerant while always be poised to vigorously respond to a microbial attack (3). The intestinal epithelium greatly facilitates this decision-making process by creating a physical barrier between luminal bacteria and underlying immune cells. The vast majority of intestinal bacteria are unable to penetrate through the mucus-coated epithelial lining, allowing immune cells to focus attention on a limited number of bacteria that manage to circumvent the barrier. However, under conditions of barrier compromise, there is a greatly increased influx of intestinal bacteria into the subepithelial space that results in direct stimulation of proinflammatory immune responses (4). These immune responses must be rapidly and potently regulated to prevent development of chronic inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn’s disease (5). Over the last decade, a remarkable number of discoveries have led to an increasingly sophisticated view of the mucosal immune regulation during homeostasis and disease (3). In PNAS, Zindl et al. (6) present another significant advance in the understanding of how immune cells regulate mucosal inflammation and promote healing. Using a mouse model of acute intestinal inflammation (colitis) induced by damage to the epithelial barrier, the authors analyzed accumulation of neutrophils and the cytokine IL-22 to establish a striking relationship between the two that ultimately leads to resolution of intestinal inflammation. In response to intestinal insult/injury, a combination of innate and adaptive immune cells are sequentially recruited and activated at sites …