STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. This study demonstrates that STAT3 activity in intestinal epithelial cells (IECs) is induced during colonic inflammation and plays a critical role in mucosal wound healing. Using genetically engineered mice, the researchers showed that epithelial STAT3 activation in dextran sodium sulfate (DSS)-induced colitis is dependent on IL-22 rather than IL-6. IL-22 is secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice showed a defect in epithelial restitution and gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. The study also shows that IL-22 is specifically induced by CD11c+ cells during acute experimental colitis. IL-22 is produced by innate immune cells, including DCs and NK cells, and plays a critical role in regulating epithelial STAT3 activity. The findings suggest that STAT3 is an important regulator of tissue homeostasis in the gut, and that STAT3 activation during acute colitis is critically dependent on IL-22. The study highlights the role of IL-22/STAT3 signaling in IECs as an important protective pathway for the mucosal immune system.STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. This study demonstrates that STAT3 activity in intestinal epithelial cells (IECs) is induced during colonic inflammation and plays a critical role in mucosal wound healing. Using genetically engineered mice, the researchers showed that epithelial STAT3 activation in dextran sodium sulfate (DSS)-induced colitis is dependent on IL-22 rather than IL-6. IL-22 is secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice showed a defect in epithelial restitution and gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. The study also shows that IL-22 is specifically induced by CD11c+ cells during acute experimental colitis. IL-22 is produced by innate immune cells, including DCs and NK cells, and plays a critical role in regulating epithelial STAT3 activity. The findings suggest that STAT3 is an important regulator of tissue homeostasis in the gut, and that STAT3 activation during acute colitis is critically dependent on IL-22. The study highlights the role of IL-22/STAT3 signaling in IECs as an important protective pathway for the mucosal immune system.