Mechanisms of Leukocyte Recruitment Into the Aorta During Atherosclerosis (original) (raw)

Atherogenesis 204 2. Multiple steps of the adhesion cascade Peripheral blood leukocytes are programmed to constitutively home to secondary lymphoid organs in search of possible antigens, in order to mount an appropriate immune response against infections. It has also been recognized that a small subset of leukocytes home into nonlymphoid tissues as a part of constitutive homing in order to sample antigens in local tissues. In line with this notion, leukocytes are found within normal/non-inflamed aortas and recent studies have demonstrated that these cells constitutively migrate into the aorta. The migration of leukocytes into non-lymphoid sites where injury, infection or inflammation has occurred is also highly specific. To date, there are several examples of immune-mediated chronic diseases such as rheumatoid arthritis, Type 1 diabetes mellitus, psoriasis, and multiple sclerosis that have marked adhesion molecule-mediated homing of leukocytes into the site of inflammation. It is now appreciated that atherosclerosis-prone conditions activate aortic vascular cells, upregulate adhesion molecules, and chemokines; thereby supporting leukocyte homing into the aorta (Galkina & Ley, 2007a)-a key step in the pathology of atherosclerosis. 2.1 Steps of the adhesion cascade 2.1.1 Selectins and rolling The adhesion cascade is defined as series of overlapping and synergistic interactions among adhesion molecules and chemokines. There are several major steps of the leukocyte adhesion cascade including selectin-dependent tethering and rolling, selectin or arrest chemokine-dependent activation, integrin-dependent arrest, firm adhesion and diapedesis, which are closely interconnected and regulate cell-specific migration. The first steps of the adhesion cascade consist of tethering, capture, and rolling, which are initiated via selectincarbohydrate ligand interactions along the endothelium (McEver, 2002). L-selectin is expressed by all leukocytes, mediates leukocyte rolling and can also participate in secondary capture, defined as leukocyte capture by adherent leukocytes (reviewed in (Ley et al., 2007)). P-and E-selectin are expressed by the activated endothelium and serve as rolling molecules for most leukocytes (McEver, 2002). Activated platelets also express P-selectin. P-selecin binds PSGL-1 expressing neutrophils, monocytes, and lymphocytes (Ley & Kansas, 2004). Eselectin binds PSGL-1, CD44, E-selectin ligand-1(ESL-1) on myeloid cells and CD43 on Thelper 1 lymphocytes (reviewed in (Ley et al., 2007)). Selectins tightly control leukocyte rolling velocity via regulation of the rapid formation and dissociation of bonds between selectins and their ligands (Alon et al., 1997). Land P-selectin support rolling at relatively fast velocities, while E-selectin supports leukocyte rolling at very slow velocities (Kunkel & Ley, 1996). Evidence suggests that selectin ligation by endothelial ligands can induce activation of integrins, and provide a link between rolling and the subsequent integrinmediated firm adhesion (Zarbock et al., 2007). 2.1.2 Integrins, arrest chemokines, and firm adhesion Following the steps of tethering and rolling, leukocyte integrins initiate slowing rolling, and induce further firm adhesion. The integrin family consists of  and  subunits that form heterodimers yielding a total of 24 integrins (Hynes, 2002). All leukocytes express leukocyte function-associated molecule (LFA-1, CD11a/CD18, or-L 2), while myeloid cells predominately express Mac-1. Endothelial ligands for LFA-1 and Mac-1 include intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. The  4  1 (VLA-4) integrin is a member of the  4