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

Abstract

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.

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

“…A pioneering work using HyPer unraveled the role of AQP3 in H 2 O 2 transport and epidermal growth factor (EGF) signaling (31). This function was recently extended to NF-κB signaling in keratinocytes (32) or in response to environmental stresses in colonic epithelia (33). Similarly, AQP8 facilitates cellular accumulation of H 2 O 2 after VEGF stimulation, thereby enhancing PI3K activity and phosphorylation of MAPKs, two essential processes for leukemia cell proliferation (34).…”

IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

“…Consistent with this idea, epithelial aquaporin-4 expression has been reported to be enhanced by IL-22 signaling (Pham et al, 2014). However, most studies have failed to identify a role for aquaporins in intestinal water transport, and, recent data suggest that intestinal epithelial aquaporins are more important for transport of bioactive signaling molecules, such as H 2 O 2 , than water (Thiagarajah et al, 2017; Yang et al, 2005). Thus, despite the potential involvement of many processes, including several activated by IL-22, in triggering the water efflux that enhances bacterial clearance, claudin-2 upregulation is the primary mechanism employed in C. rodentium colitis.…”

Dual oxidase: a novel therapeutic target in allergic disease

“…Another issue with respect to the proposed involvement of DUOX or other NOX isozymes in cellular redox signalling is the fact that NOX‐derived ROS are generated extracellularly or within phagosomes/endosomes and are thus segregated from their putative cytoplasmic redox‐sensitive targets by a lipid membrane. The recent discovery of aquaporins as selective channels for H 2 O 2 resolves this issue, and aquaporin‐dependent transmembrane H 2 O 2 transfer likely helps confine the oxidative potential of H 2 O 2 to assure specificity in redox signalling (Bertolotti et al ., ; Thiagarajah et al ., ).…”