Chemokine receptor activation also activates phosphatidylinositol 3-kinase (PI3K) isoforms, gamma and delta, which convert PIP2 to phosphatidylinositol 3,4,5-trisphosphate (PIP3). RIAM is a member of the MRL (MIG-10, RIAM, lamellipodin) family of adapter proteins. This recruitment can be both direct, via Rap1-talin interactions, or indirect, via intermediate proteins such as Rap1-interacting adapter molecule (RIAM). Rap1a and b are small GTPases coordinated by CalDAG-GEF1 and are the principal effectors of the activation of integrin adhesion as they lead to recruitment of talin-1 to the plasma membrane. The liberation of DAG and the release of calcium from the endoplasmic reticulum in response to IP3 formation together lead to activation of a Guanine Exchange Factor (GEF) called calcium and DAG-regulated GEF1 (CalDAG-GEF1). PLC converts the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG), leading to activation of important downstream regulators including the cascade that leads to activation of the β2 integrin. This recognition results in the separation of Gαi from the beta and gamma subunits of the GPCR, which activates phospholipase C (PLC). Chemokine signaling starts with chemokines such as IL-8 binding to G-protein coupled receptors (GPCRs) such as CXCR1 and CXCR2. The selectin-based signals result from neutrophil selectin, PSGL-1 engagement with the endothelial selectins, which leads to recruitment of proteins DAP12 and FcRgamma, and activation of Syk and Src kinases. Integrin activation requires the recruitment and activation of the proteins talin-1 and kindlin-3 to the plasma membrane. Migration, spreading, phagocytosis and activation of the respiratory burst require outside–in signaling.īoth selectin- and chemokine-induced signals converge and trigger dramatic conformational changes that result in full β2 integrin activation by inside–out signaling. Chemokine-triggered arrest from rolling must rely on inside–out signaling, because resting integrins cannot mediate outside–in signaling. αLβ2 is critical for neutrophil adhesion, while αMβ2 is involved in neutrophil migration, spreading, phagocytosis and activation of the respiratory burst (superoxide production). These two integrins have overlapping but also distinguishable roles during neutrophil arrest and migration and phagocytosis. Neutrophils express mainly two of the four β2 integrins, αLβ2 and αMβ2. Over the years the names of these integrin receptors have changed but are standardized now as αLβ2, αMβ2, αXβ2 and αDβ2 and this nomenclature is used here. Some monocytes also express αXβ2 (CD11c/CD18, also known as complement receptor 4, CR4). Myeloid cells also express αMβ2 (CD11b/CD18, also known as macrophage-1 antigen, Mac-1, or complement receptor 3, CR3). All leukocytes express αLβ2 (CD11a/CD18), also known as lymphocyte-function-associated antigen 1, LFA-1). There are four distinct α-subunits, αL, αM, αX and αD (or CD11a-d) that can pair with the same common β2 integrin subunit to form four distinct β2 integrin leukocyte receptors. Each integrin recognizes, and connects to ICAM-1, ICAM-2 and ICAM-3 on endothelial cells and couples to the cells’ intracellular cytoskeletal and signaling machineries. Integrins are heterodimeric adhesion receptors consisting of α- and β-subunits that are expressed on the plasma membrane. They form a sub-class of the integrin family of CAMs. Β2 integrins (also known as CD18) are expressed by all leukocyte types. The integrin conformation during this slow rolling is not known, but this conformation appears to require talin-1 and not kindlin-3. Transient engagement of β2 integrins with intercellular cell adhesion molecules (ICAMs) on vascular endothelium significantly reduces the rolling velocity. The leukocyte rolling enables the cells to survey the area, and permits the interaction of leukocytes with immobilized chemokines that trigger β2 integrin activation, leading to neutrophil arrest. During inflammation, chemokines such as IL-8 are released by macrophages in inflamed tissues and become immobilized on the endothelial surface. Following attachment to the endothelial cells, the rapidly reversible interaction of selectins with their ligands on the vessel wall provides the mechanical basis of leukocyte rolling. Neutrophils express P-selectin glycoprotein ligand-1 (PSGL1, CD162) that binds all 3 selectins: P-selectin on endothelial cells and platelets, E-selectin on endothelial cells, and L-selectin on leukocytes. Neutrophil rolling is mediated by the selectin family of CAMs which orchestrate the interactions between circulating cells and the endothelium.
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