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 of tissue damage. These immune cells initially protect the host from microbial invasion and further tissue damage; however, intestinal bacteria and injured cells also act as danger signals to alert the immune system to respond in a proinflammatory manner (5). Thus, some of the immune cells that infiltrate the intestine following injury may initially worsen tissue damage. Of the numerous immune cells that are recruited to the intestine during inflammation, neutrophils are among the first responders (7). While recruitment of neutrophils to sites of intestinal injury or microbial invasion is a crucial component of the inflammatory response, migration of neutrophils across the epithelium is associated with disruption of barrier function that can increase recruitment of more neutrophils due to enhanced leakage of luminal contents into the mucosa (8, 9). Furthermore, neutrophils that are activated by microbial products release proinflammatory mediators such as chemokines/ cytokines including IL-8, growth-regulated oncogene (GRO)α, macrophage inflammatory protein (MIP)1α, TNFα, IL-1β and lipid mediators such as leukotriene B4 (LTB4) that havemultiple consequences including recruitment and activation of other leukocytes (10). In addition to promoting recruitment of defending leukocytes, neutrophils that phagocytose bacteria and microbial products release copious amounts of reactive oxygen species (ROS) into the immediate tissue environment. Superoxide anion produced by an NADPH oxidase is rapidly converted to hydrogen peroxide, which, in turn, is modified to hypochlorous acid by myeloperoxidase released from exocytosed neutrophils granules. These ROS damage nearby cells/tissue by indiscriminately oxidizing/chlorinating proteins and damaging DNA. Furthermore, the granules released by activated neutrophils also contain potent peptides and enzymes that not only help kill microbes but also degrade proteins and attract additional leukocytes. One abundant enzyme released from degranulating neutrophils is elastase, which has been shown to degrade barrier-forming proteins on epithelial cells.