Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1β, and atrophic gastritis in mice.

Abstract

Although defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. We generated knockout mice of stomach-type claudin-18, a major component of TJs in the stomach. Cldn18(-/-) mice were afflicted with atrophic gastritis that started on postnatal day 3. This coincided with a decrease in intragastric pH due to H(+) secretion from parietal cells and concomitant up-regulation of the cytokines, interleukin-1β, cyclooxygenase-2, and KC, resulting in spasmolytic polypeptide-expressing metaplasia (SPEM). Oral administration of hydrochloric acid on postnatal day 1 induced the expression of these cytokines in Cldn18(-/-) infant stomach, but not in Cldn18(+/+) mice. A paracellular H(+) leak in Cldn18(-/-) stomach was detected by electrophysiology and H(+) titration, and freeze-fracture electron microscopy showed structural defects in the TJs, in which the tightly packed claudin-18 (stomach-type)-based TJ strands were lost, leaving a loose meshwork of strands consisting of other claudin species. These findings provide evidence that claudin-18 normally forms a paracellular barrier against H(+) in the stomach and that its deficiency causes paracellular H(+) leak, a persistent up-regulation of proinflammatory cytokines, chronic recruitment of neutrophils, and the subsequent development of SPEM in atrophic gastritis.