The use of lymphocyte function-associated antigen (LFA)-1-deficient mice to determine the role of LFA-1, Mac-1, and alpha 4 integrin in the inflammatory response of neutrophils

After injury or infection, neutrophils rapidly migrate from the circulation into tissues by means of an orderly progression of adhesion receptor engag ements. Neutrophils have been previously considered to use selectins exclus ively to roll on vessels before an adhesion step mediated by the beta2 inte grins, lymphocyte function-associated antigen (LFA)-1, and Mac-1. Here we u se LFA-1(-/-) mice, function blocking monoclonal antibodies, and intravital microscopy to investigate the roles of LFA-1, Mac-1, and alpha4 integrins in neutrophil recruitment in vivo. For the first time, we show that LFA-1 m akes a contribution to neutrophil rolling by stabilizing the transient atta chment or tethering phase of rolling. In contrast, Mac-1 does not appear to be important for tither rolling or firm adhesion, but instead contributes to emigration from the vessel. Blocking Mac-1 in the presence of LFA-1 sign ificantly reduces emigration, suggesting cooperation between these two inte grins. Low levels of alpha4 beta1 integrin can be detected on neutrophils f rom LFA-1(+/+) and (-/-) mice. These cells make use alpha4 beta1 during the rolling phase, particularly in the absence of LFA-1. Thus LFA-1 and cr-l p l, together with the selectins, are involved in the rolling phase of neutro phil recruitment, and, in turn, affect the later stages of the transmigrati on event.