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Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia

Significance The extracellular production of hydrogen peroxide (H2O2) by membrane or secreted oxidases has been linked to epithelial wound repair, defense against infection, and inflammation. Here, we elucidate the pathway that explains how extracellular H2O2 transduces a signal into the cell to induce these critical cell functions. Our study shows the central component of this pathway in the mammalian colon is the H2O2-conducting aquaglyceroporin AQP3 and implicates this channel in innate immune responses at mucosal surfaces. The colonic epithelium provides an essential barrier against the environment that is critical for protecting the body and controlling inflammation. In response to injury or gut microbes, colonic epithelial cells produce extracellular hydrogen peroxide (H2O2), which acts as a potent signaling molecule affecting barrier function and host defense. In humans, impaired regulation of H2O2 in the intestine has been associated with early-onset inflammatory bowel disease and colon cancer. Here, we show that signal transduction by H2O2 depends on entry into the cell by transit through aquaporin-3 (AQP3), a plasma membrane H2O2-conducting channel. In response to injury, AQP3-depleted colonic epithelial cells showed defective lamellipodia, focal adhesions, and repair after wounding, along with impaired H2O2 responses after exposure to the intestinal pathogen Citrobacter rodentium. Correspondingly, AQP3−/− mice showed impaired healing of superficial wounds in the colon and impaired mucosal innate immune responses against C. rodentium infection, manifested by reduced crypt hyperplasia, reduced epithelial expression of IL-6 and TNF-α, and impaired bacterial clearance. These results elucidate the signaling mechanism of extracellular H2O2 in the colonic epithelium and implicate AQP3 in innate immunity at mucosal surfaces.