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Updated: Mar 22, 2026
Analyzing the Effects of Stromal Cells on the Recruitment of Leukocytes from Flow
Published on: January 7, 2015
Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces bacterial spread during polymicrobial
Hemant K Mishra1, Timothy J Johnson1, Davis M Seelig2
1Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and.
Abstract:
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-α 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.
Insights
Sepsis impairs neutrophil recruitment, but blocking a disintegrin and metalloprotease-17 (ADAM17) in leukocytes improves survival. Reduced bacterial spread and inflammation were observed in ADAM17-deficient mice, highlighting its role in sepsis severity.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Neutrophil recruitment is crucial for fighting infection but is impaired during sepsis.
- Sepsis involves systemic inflammation and reduced immune cell function.
- Leukocyte activation during sepsis induces a disintegrin and metalloprotease-17 (ADAM17) activity.
Purpose of the Study:
- To investigate the role of ADAM17 in leukocyte function during sepsis.
- To determine if inhibiting ADAM17 in leukocytes improves sepsis outcomes.
Main Methods:
- Conditional knockout mice lacking ADAM17 in leukocytes were subjected to polymicrobial sepsis.
- Survival rates, bacterial load, cytokine levels, and neutrophil recruitment were assessed.
Main Results:
- Conditional knockout mice lacking ADAM17 in leukocytes showed improved survival during sepsis.
- Bacteremia and pro-inflammatory cytokine levels were significantly reduced in knockout mice.
- Peritoneal bacterial spread was reduced, with enhanced neutrophil recruitment observed in knockout mice.
Conclusions:
- ADAM17 activity in leukocytes significantly contributes to sepsis severity.
- Inhibiting ADAM17 in leukocytes enhances neutrophil recruitment and improves outcomes during sepsis.
- Targeting ADAM17 may offer a therapeutic strategy for sepsis.
