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Proteolytic shedding by ADAM 17 (TACE) functions as a gatekeeper for leukocyte emigration to inflammatory sites
Author(s) -
Raines Elaine W.,
Tang Jingjing,
Zarbock Alexander,
Gomez Ivan,
Bell Bridgit,
Ley Klaus,
Wilson Carole L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.166.4
Subject(s) - monocyte , microbiology and biotechnology , inflammation , peritoneal cavity , peritoneum , infiltration (hvac) , biology , immunology , integrin alpha m , chimera (genetics) , chemistry , immune system , anatomy , biochemistry , gene , physics , thermodynamics
Leukocyte recruitment to inflammatory sites involves sequential adhesive interactions associated with dynamic changes in expression and function of cell surface proteins. We hypothesize that proteolysis of cell surface proteins allows instantaneous uncoupling of adhesive and signaling events, and thus is a key regulator of the inflammatory response. To test this hypothesis, the sterile irritant thioglycollate was injected into the peritoneum of hematopoietic mouse chimeras that lack the sheddase ADAM17 in circulating cells. Thioglycollate injection first initiates neutrophil emigration into the peritoneal cavity, and at 4 hr Ly6G+ neutrophils are increased by 75% in null chimeras. ADAM17‐/‐ chimeras also display a 50% decrease in rolling velocity and a 2‐fold increase in adherent cells visualized by intravital microscopy of the cremaster muscle. In contrast with accelerated neutrophil emigration, monocyte (CD11b+/Ly6G‐) infiltration in null chimeras is reduced by 25% at 48–72 hr, a time of maximal monocyte accumulation. Studies of mixed hematopoietic chimeras (50% wild type, 50% null) further implicate ADAM17 in promoting macrophage exit from the peritoneum. Together these data reveal that ADAM17's function in wild type mice is critical for restriction of neutrophil infiltration, and promotion of monocyte emigration and resolution of the inflammatory response. (Supported by HL67267 & HL18645)