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ADAM17 regulates CXCR2 surface levels in circulating neutrophils and their infiltration into sites of inflammation. The chemokine receptor CXCR2 is expressed at high levels on circulating neutrophils and is critical for directing their migration to sites of inflammation. CXCR2 surface levels are rapidly modulated by 2 mechanisms—cell internalization and recycling upon ligand binding—and by a metalloprotease activity following overt neutrophil activation by nonligand stimuli. The latter process has only been described in human neutrophils, and essentially, nothing is known about its functional relevance and the specific protease involved. We show that targeting ADAM17 in mouse and human neutrophils blocks CXCR2 down‐regulation induced by nonligand stimuli but not by chemokine ligands. This was determined by use of a selective ADAM17 inhibitor, an ADAM17 function‐blocking antibody, and ADAM17 gene‐targeted mice. CXCR2 is known to undergo a marked down‐regulation during various inflammatory disorders, and this is associated with impaired neutrophil recruitment. We show that blocking ADAM17 activity reduced CXCR2 down‐regulation on circulating neutrophils and enhanced their recruitment during acute inflammation, which was reversed by a CXCR2 inhibitor. Taken together, our findings demonstrate that unlike CXCR2 internalization, ADAM17 induction down‐regulates the receptor in an irreversible manner and may serve as a master switch in controlling CXCR2 function, but may also contribute to neutrophil dysfunction during excessive inflammation.

E‐selectin is expressed by the vascular endothelium and binds flowing neutrophils in the blood to facilitate their recruitment into the underlying tissue at sites of inflammation. L‐selectin on neutrophils is engaged by E‐selectin and undergoes rapid clustering and then coalescence in the trailing edge of polarizing cells. These processes are believed to increase the valency and capacity of L‐selectin to signal CD18 integrin activity. Neutrophils, upon exiting the microvasculature, down‐regulate their surface L‐selectin through ectodomain shedding by a disintegrin and metalloprotease 17 (ADAM17). We reasoned that neutrophil tethering and rolling on E‐selectin might initiate a coordinate change in the membrane distribution of ADAM17 as well. We found that ADAM17 indeed underwent a dramatic cell surface redistribution to the trailing edge of neutrophils rolling on purified E‐selectin when activated by a chemoattractant under shear flow; however, its lateral migration occurred at a slower rate than L‐selectin. ADAM17 and L‐selectin also redistributed in the same manner in neutrophils attached to IL‐1β‐stimulated HUVEC under shear flow. In contrast, the coalescence of L‐selectin on the surface of neutrophils by antibody cross‐linking did not promote the redistribution of ADAM17, suggesting that these molecules do not constitutively associate in the plasma membrane. Together, our findings reveal that neutrophil activation upon E‐selectin adhesion initiates active transport of ADAM17 and L‐selectin to the cell uropod, thus providing additional insight into the molecular mechanisms that regulate L‐selectin during leukocyte extravasation.