Abstract
Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.
Highlights
Neutrophils are critical effector cells of the innate immune response and recruited to sites of tissue injury in response to locally generated chemoattractants
Human granulocytes express CD13 on their cell surface [14, 15] and we have previously shown the existence of an inverse correlation between neutrophil CD13 activity and the proapoptotic efficacy of tumor necrosis factor-α (TNF-α), and the ability of CD13 inhibitors to enhance this response [16]
We demonstrate the novel observation of neutrophil homotypic aggregation (HA) in response to anti-CD13 monoclonal antibody (mAb) and a resultant reduction in chemoattractant-induced migration through collagen I
Summary
Neutrophils are critical effector cells of the innate immune response and recruited to sites of tissue injury in response to locally generated chemoattractants. Human granulocytes express CD13 on their cell surface [14, 15] and we have previously shown the existence of an inverse correlation between neutrophil CD13 activity and the proapoptotic efficacy of tumor necrosis factor-α (TNF-α), and the ability of CD13 inhibitors to enhance this response [16]. This is the only reported function of CD13 in human neutrophils. We demonstrate the novel observation of neutrophil HA in response to anti-CD13 mAbs and a resultant reduction in chemoattractant-induced migration through collagen I
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