Abstract
Neutrophils are specialized at killing bacteria and are recruited from the blood in a rapid and robust manner during infection. A cascade of adhesion events direct their attachment to the vascular endothelium and migration into the underlying tissue. A disintegrin and metalloproteinase 17 (ADAM17) functions in the cell membrane of neutrophils and endothelial cells by cleaving its substrates, typically in a cis manner, at an extracellular site proximal to the cell membrane. This process is referred to as ectodomain shedding and it results in the downregulation of various adhesion molecules and receptors, and the release of immune regulating factors. ADAM17 sheddase activity is induced upon cell activation and rapidly modulates intravascular adhesion events in response to diverse environmental stimuli. During sepsis, an excessive systemic inflammatory response against infection, neutrophil migration becomes severely impaired. This involves ADAM17 as indicated by increased levels of its cleaved substrates in the blood of septic patients, and that ADAM17 inactivation improves neutrophil recruitment and bacterial clearance in animal models of sepsis. Excessive ADAM17 sheddase activity during sepsis thus appears to undermine in a direct and indirect manner the necessary balance between intravascular adhesion and de-adhesion events that regulate neutrophil migration into sites of infection. This review provides an overview of ADAM17 function and regulation and its potential contribution to neutrophil dysfunction during sepsis.
Highlights
Reviewed by: Elizabeth Gardiner, Australian National University, Australia Susan M
It has been reported that the plasma levels of several leukocyte- and endothelial cell-expressed, A disintegrin and metalloproteinase 17 (ADAM17) substrates are significantly elevated during sepsis, including L-selectin, ICAM-1, VCAM-1, CD16b, TNFα, IL-6R, TNFRI, and TNFRII, and some of these substrates demonstrated a positive correlation with disease severity (Ertel et al, 1994; Muller Kobold et al, 1998; Schulte et al, 2013; Zonneveld et al, 2014; Lerman and Kim, 2015)
ADAM17 substrates on neutrophils and endothelial cells include L-selectin, CXCR2, CD16b, JAMA, ICAM1, PECAM1, and VCAM1, and the sheddase appears to function as a pivotal regulator of intravascular adhesion events (Figure 1A)
Summary
Reviewed by: Elizabeth Gardiner, Australian National University, Australia Susan M. This involves ADAM17 as indicated by increased levels of its cleaved substrates in the blood of septic patients, and that ADAM17 inactivation improves neutrophil recruitment and bacterial clearance in animal models of sepsis.
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