Molecular mechanisms regulating CD 13‐mediated adhesion

Summary CD 13/Aminopeptidase N is a transmembrane metalloproteinase that is expressed in many tissues where it regulates various cellular functions. In inflammation, CD 13 is expressed on myeloid cells, is up‐regulated on endothelial cells at sites of inflammation and mediates monocyte/endothelial adhesion by homotypic interactions. In animal models the lack of CD 13 alters the profiles of infiltrating inflammatory cells at sites of ischaemic injury. Here, we found that CD 13 expression is enriched specifically on the pro‐inflammatory subset of monocytes, suggesting that CD 13 may regulate trafficking and function of specific subsets of immune cells. To further dissect the mechanisms regulating CD 13‐dependent trafficking we used the murine model of thioglycollate‐induced sterile peritonitis. Peritoneal monocytes, macrophages and dendritic cells were significantly decreased in inflammatory exudates from global CD 13 KO animals when compared with wild‐type controls. Furthermore, adoptive transfer of wild‐type and CD 13 KO primary myeloid cells, or wild‐type myeloid cells pre‐treated with CD 13‐blocking antibodies into thioglycollate‐challenged wild‐type recipients demonstrated fewer CD 13 KO or treated cells in the lavage, suggesting that CD 13 expression confers a competitive advantage in trafficking. Similarly, both wild‐type and CD 13 KO cells were reduced in infiltrates in CD 13 KO recipients, confirming that both monocytic and endothelial CD 13 contribute to trafficking. Finally, murine monocyte cell lines expressing mouse/human chimeric CD 13 molecules demonstrated that the C‐terminal domain of the protein mediates CD 13 adhesion. Therefore, this work verifies that the altered inflammatory trafficking in CD 13 KO mice is the result of aberrant myeloid cell subset trafficking and further defines the molecular mechanisms underlying this regulation.