The Use of Lymphocyte Function–Associated Antigen (Lfa)-1–Deficient Mice to Determine the Role of Lfa-1, Mac-1, and α4 Integrin in the Inflammatory Response of Neutrophils

Abstract

After injury or infection, neutrophils rapidly migrate from the circulation into tissues by means of an orderly progression of adhesion receptor engagements. Neutrophils have been previously considered to use selectins exclusively to roll on vessels before an adhesion step mediated by the β2 integrins, lymphocyte function–associated antigen (LFA)-1, and Mac-1. Here we use LFA-1−/− mice, function blocking monoclonal antibodies, and intravital microscopy to investigate the roles of LFA-1, Mac-1, and α4 integrins in neutrophil recruitment in vivo. For the first time, we show that LFA-1 makes a contribution to neutrophil rolling by stabilizing the transient attachment or tethering phase of rolling. In contrast, Mac-1 does not appear to be important for either rolling or firm adhesion, but instead contributes to emigration from the vessel. Blocking Mac-1 in the presence of LFA-1 significantly reduces emigration, suggesting cooperation between these two integrins. Low levels of α4β1 integrin can be detected on neutrophils from LFA-1+/+ and −/− mice. These cells make use of α4β1 during the rolling phase, particularly in the absence of LFA-1. Thus LFA-1 and α4β1, together with the selectins, are involved in the rolling phase of neutrophil recruitment, and, in turn, affect the later stages of the transmigration event.

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

“…Gamma delta (c d) T cells, which also express high levels of LFA-1, are particularly abundant in the resident lymphocyte population of the liver (47) and have been shown to be important for priming of CD8 + T cells in response to infection (48). In addition, many of the effectors of innate immunity such as neutrophils and macrophages rely on LFA-1 for vascular adhesion and rolling prior to emigration into tissues (49)(50)(51). Such effectors of innate immunity which comprise early inflammatory events can significantly influence T-cell recruitment and acute allograft rejection (52).…”

Two Functional Active Conformations of the Integrin α2β1, Depending on Activation Condition and Cell Type

“…There is some evidence for other integrins that certain conformational states are likely to be more suited for a transient adhesion like cell spreading, rolling, and migration, whereas other conformations favor a more stable adhesion. For example, it has been demonstrated that the integrin ␣L␤2 can support such a transient adhesion of leukocytes (namely rolling), together with selectins and ␣4 integrins, during inflammation in vivo (52). More recently, this observation could be linked to a certain conformational state of ␣L␤2.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Fully activated LFA-1 mediates the stop of rolling and makes firm adhesion along with Mac-1 (175). Deficiency of b 2 integrin chain causes Leukocyte Adhesion Deficiency Type 1, an inherited disorder that is characterized by inability of leukocytes to undergo adhesion-dependent migration (49).…”