title: ADAM17 activation in circulating neutrophils following bacterial challenge impairs their recruitment.
abstract: Neutrophil infiltration and bacterial clearance occur earlier in conditional knockout mice with leukocytes lacking the metalloprotease ADAM17 than in control mice. We investigated cell-intrinsic changes in neutrophils lacking ADAM17 and alterations in the inflammatory environment in conditional ADAM17 knockout mice to determine how the sheddase exerts its effects on neutrophil recruitment. In vivo analyses comparing control and ADAM17-deficient neutrophils revealed that the latter cells accumulated at increased levels in the inflamed mesenteric microvasculature and in the peritoneal cavity following bacterial challenge, indicating changes in their adhesive properties. Consistent with this, bacterial infection caused a marked down-regulation of L-selectin, an adhesion protein and substrate of ADAM17, from the surface of circulating neutrophils in control mice but not in conditional ADAM17 knockout mice. Neutrophils from gene-targeted mice with leukocytes expressing a noncleavable form of L-selectin also displayed a competitive advantage in the presence of control neutrophils when infiltrating a site of infection. Taken together, our findings reveal that impaired L-selectin shedding is a key mechanism underlying early neutrophil recruitment in conditional ADAM17 knockout mice during bacterial infection. Disrupting only the shedding of L-selectin, however, did not increase bacterial clearance, indicating that additional substrates also contribute to the detrimental role of ADAM17 during severe infection.
authors.affiliation: Departments of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Long
authors.forename: M Reza
authors.initials: MR
authors.lastname: Hosseinkhani
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Sriramarao
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
mesh_terms: D051722:ADAM Proteins / Q000276:immunology* / Q000378:metabolism; D000072198:ADAM17 Protein; D019264:Adoptive Transfer; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse