In vivo role of leukocyte ADAM17 in the inflammatory and host responses during E. coli-mediated peritonitis

Journal of Leukocyte Biology

Chunmei Long¹  Amy H. Herrera¹  Keisuke Horiuchi²  Bruce Walcheck¹  Yue Wang¹ 

[1] Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and;Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, Japan Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, Japan Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, Japan

关键词: inflammation;    sepsis;    neutrophil;    ectodomain shedding;    TACE;    TNF-α;   

DOI  :  10.1189/jlb.1109763

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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-α 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.

【 授权许可】

Unknown