Husky (Luxembourg)

SummaryAlthough the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.

Abstract This study reports a new and significantly enhanced analysis of US flood hazard at 30 m spatial resolution. Specific improvements include updated hydrography data, new methods to determine channel depth, more rigorous flood frequency analysis, output downscaling to property tract level, and inclusion of the impact of local interventions in the flooding system. For the first time, we consider pluvial, fluvial, and coastal flood hazards within the same framework and provide projections for both current (rather than historic average) conditions and for future time periods centered on 2035 and 2050 under the RCP4.5 emissions pathway. Validation against high‐quality local models and the entire catalog of FEMA 1% annual probability flood maps yielded Critical Success Index values in the range 0.69–0.82. Significant improvements over a previous pluvial/fluvial model version are shown for high‐frequency events and coastal zones, along with minor improvements in areas where model performance was already good. The result is the first comprehensive and consistent national‐scale analysis of flood hazard for the conterminous US for both current and future conditions. Even though we consider a stabilization emissions scenario and a near‐future time horizon, we project clear patterns of changing flood hazard (3 σ changes in 100 years inundated area of −3.8 to +16% at 1° scale), that are significant when considered as a proportion of the land area where human use is possible or in terms of the currently protected land area where the standard of flood defense protection may become compromised by this time.