Abstract

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.

Highlights

  • Sepsis is a complex and heterogenous clinical syndrome caused by a highly disrupted immune response during severe infection [1]

  • A number of studies have shown, that the highly efficient manner of neutrophil influx into sites of infection can become compromised during sepsis, a type of dysfunction that has been referred to as neutrophil paralysis [8]

  • We investigated for the first time the in vivo effects of systemic ADAM17 inhibition using a function blocking monoclonal antibody on sepsis resistance

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Summary

Introduction

Sepsis is a complex and heterogenous clinical syndrome caused by a highly disrupted immune response during severe infection [1]. A number of studies have shown, that the highly efficient manner of neutrophil influx into sites of infection can become compromised during sepsis, a type of dysfunction that has been referred to as neutrophil paralysis [8]. Mice with ADAM17-null leukocytes showed significantly improved survival during monomicrobial and polymicrobial sepsis [15,16,17], and this increased resistance corresponded with higher neutrophil recruitment at sites of infection and decreased bacterial levels locally and systemically [15,16,17]. In patients, ADAM17 activity and a functional polymorphism of its gene corresponded with sepsis progression [18,19]. We have shown MEDI3622 recognizes mouse as well as human leukocytes and effectively blocks ectodomain shedding of ADAM17 substrates [22]. We found that the combined treatments markedly increased survival, neutrophil infiltration at the site of infection, and reduced systemic cytokine levels and their proinflammatory profile

Administration of a mAb That Blocks ADAM17 Function Increases Sepsis Survival
MEDI3622 Administration Post-CLP Prolongs Survival
Animals
Administration of MEDI3622 and Antibiotics
Quantification of Plasma Analytes
Enumeration of Blood and Peritoneal Fluid Levels of Neutrophils and Bacteria
Statistical Analysis
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