˜°LFA-1 Integrins Bind to cell-adhesion molecules and extracellular matrix. Strong adhesion Monocytes, macrophages Fibronectin ˜5:°1 (VLA-5, CD49d:CD29) Monocytes, T cells, macrophages, neutrophils, dendritic cells, NK cells Neutrophils, monocytes, macrophages, NK cells Dendritic cells, macrophages, neutrophils, NK cells ICAM-1, ICAM-2 ICAM-1, iC3b, ÿbrinogen iC3b ˜L:°2 (LFA-1, CD11a:CD18) ˜M:°2 (CR3, Mac-1, CD11b:CD18) ˜X:°2 (CR4, p150.95, CD11c:CD18) of two transmembrane protein chains, α and β, of which there are numerous different types. Subsets of integrins have a common β chain partnered with different α chains. The leukocyte integrins important for extravasation are LFA-1 (αL:β2, also known as CD11a:CD18) and CR3 (αM:β2, complement receptor type 3, also known as CD11b:CD18 or Mac-1). We described CR3 in Section 2-13 as a receptor for iC3b, but it also binds other ligands. Both LFA-1 and CR3 bind to ICAM-1 and to ICAM-2 (Fig. 3.30). Even in the absence of infection, circulating monocytes are continuously leaving the blood and entering certain tissues, such as the intestine, where they become resident macrophages. To navigate out of the blood vessel, they may adhere to ICAM-2, which is expressed at low levels by unactivated endothelium. CR3 also binds to fibrinogen and factor X, both substrates of the coagulation cascade.
Strong adhesion between leukocytes and endothelial cells is promoted by the induction of ICAM-1 on inflamed endothelium together with a conformational change in LFA-1 and CR3 that occurs on the leukocyte. Integrins can switch between an ‘active’ state, in which they bind strongly to their ligands, and an ‘inactive’ state, in which binding is easily broken. This enables cells to make and break integrin-mediated adhesions in response to signals received by the cell either through the integrin itself or through other receptors. In the activated state, an integrin molecule is linked via the intracellular protein talin to the actin cytoskeleton. In the case of migrating leukocytes, chemokines binding to their receptors on the leukocyte generate intracellular signals that cause talin to bind to the cytoplasmic tails of the β chains of LFA-1 and CD3, forcing the integrin extracellular regions to assume an active binding conformation. The importance of leukocyte integrin function in inflammatory cell recruitment is illustrated by leukocyte adhesion deficiencies, which can be caused by defects in the integrins themselves or in the proteins required for modulating adhesion. People with these diseases suffer from recurrent bacterial infections and impaired healing of wounds.