In vivo role of leukocyte ADAM17 in the inflammatory and host responses during E. coli-mediated peritonitis.
Long Chunmei,Wang Yue,Herrera Amy H,Horiuchi Keisuke,Walcheck Bruce
Journal of leukocyte biology
Inflammation is the body's initial response to infection, which is harmful when excessive, as exemplified in sepsis inflammatory syndromes. Ectodomain shedding by the membrane metalloprotease ADAM17 is an emerging regulator of inflammation, as it directs the activity of various inflammatory modulators. At this time, however, little is known about the in vivo function of ADAM17. Here, we show that ADAM17-deficient leukocytes afforded mice a survival benefit following Escherichia coli-mediated peritoneal sepsis, which was associated with a reduction in systemic proinflammatory cytokine levels and bacterial burden. A more rapid yet transitory neutrophil infiltration into the peritoneal cavity of conditional ADAM17 knockout mice was observed when compared with control mice, suggesting a mechanism for their enhanced clearance of bacteria. Preventing the shedding of L-selectin augments neutrophil recruitment, and we show that L-selectin shedding by peritoneal neutrophils in conditional ADAM17 knockout mice was impaired. Moreover, their peritoneal TNF-alpha levels were markedly lower than control mice following E. coli challenge. These events indicate key molecular processes involved in the altered time course of neutrophil recruitment in conditional ADAM17 knockout mice. Overall, our study provides novel in vivo evidence of the instrumental role of ADAM17 in modulating inflammation and host resistance during Gram-negative bacterial infection.