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Regulating inflammation in acute lung injury
S55 The Aminopeptidase CD13 Regulates Homotypic Aggregation of Neutrophils
  1. CA Fiddler1,
  2. G Murphy2,
  3. AS Cowburn1,
  4. H Parfrey1,
  5. ER Chilvers1
  1. 1Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK
  2. 2Department of Oncology, University of Cambridge, Cambridge, UK


Neutrophils are critical effector cells of the innate immune response and are recruited to sites of tissue injury in response to locally generated chemoattractants. Neutrophil recruitment is a highly regulated process involving complex interactions with the vascular endothelium and underlying tissue stroma. In addition to adhering to the endothelium, neutrophils can also self-associate, (a process known as homotypic aggregation - HA), which has been proposed to play a key role in disease states such as sepsis.

Aminopepetidase N or CD13 is a widely expressed membrane-bound metallopeptidase involved in the migration and invasion of cancer and endothelial cells. Neutrophils express CD13 on their cell surface, which is upregulated by TNF-α, IL-8 and fMLP We have shown that inhibition of aminopeptidase activity enhances the efficacy of TNF-α-induced neutrophil apoptosis (Cowburn et al. J Biol Chem 2006; 281:12458). Cross-linking anti-CD13 monoclonal antibodies (mAb) have been shown to induce HA of monocytic cells through PI3K activation (Mina-Osorio et al. J Leuk Biol 2006; 79:719). We hypothesised that CD13 may be involved in neutrophil migration and HA.

Using plasma-Percoll purified human neutrophils and a modified Boyden filtre assay we showed that IL-8 mediated neutrophil chemotaxis was not affected by either the CD13 mAb WM-15 or the aminopeptidase enzymatic inhibitor bestatin. In contrast, IL-8-mediated neutrophil migration through type 1 collagen gels was significantly impaired by WM-15 and MY7 mAbs, which both inhibit enzymatic activity and induce clustering of CD13. The non-clustering CD13 antibody WM-47 and bestatin had no effect. WM-15 and MY7 also promoted neutrophil aggregation as assessed by light microscopy. Phase-contrast video-microscopy demonstrated that in WM-15 treated neutrophils, where HA was evident, the percentage of cells entering collagen 1 gels in response to IL-8 was significantly reduced (26.9% vs 71.8% in non-HA cells). WM-15 does not prime neutrophils, as assessed by superoxide production and shape change, and the cell surface expression of CD11b, CD18 and CD66b were not altered. These data suggest a novel role for CD13 in the homotypic aggregation of neutrophils, which reduces chemoattractant-induced migration through collagen 1 matrix and may predispose to neutrophil micro-aggregation within the circulation.

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