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Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces
bacterial spread during polymicrobial sepsis
#MMPMID27059842
Mishra HK
; Johnson TJ
; Seelig DM
; Walcheck B
J Leukoc Biol
2016[Nov]; 100
(5
): 999-1004
PMID27059842
show ga
A rapid and robust recruitment of circulating neutrophils at sites of infection
is critical for preventing bacterial spread. The efficiency of this process,
however, is greatly diminished during sepsis, a severe systemic inflammatory
response to infection. The proteolytic activity of a disintegrin and
metalloprotease-17 is induced in the cell membrane of leukocytes upon their
activation, resulting in the conversion of membrane to soluble TNF-? and the
release of assorted receptors from the surface of neutrophils important for their
effector functions. We show that conditional knockout mice lacking a disintegrin
and metalloprotease-17 in all leukocytes had a survival advantage when subjected
to polymicrobial sepsis. Bacteremia and the levels of circulating proinflammatory
cytokines, key determinants of sepsis severity, were significantly reduced in
conditional a disintegrin and metalloprotease-17 knockout mice during sepsis.
Although cecal bacterial microbiota and load were similar in unmanipulated
conditional a disintegrin and metalloprotease-17 knockout and control mice,
peritoneal spread of bacteria was significantly reduced in conditional a
disintegrin and metalloprotease-17 knockout mice following sepsis induction,
which was associated with an amplified recruitment of neutrophils. Taken
together, our findings suggest that extensive a disintegrin and
metalloprotease-17 induction during sepsis may tip the balance between efficient
and impaired neutrophil recruitment.
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