Selectin-Mediated Signaling-Shedding Light on the Regulation of Integrin Activity in Neutrophils

Abstract

As a consequence of tissue injury or infection, neutrophils are recruited in a stepwise recruitment process from the bloodstream into the surrounding tissue. Selectins are a family of adhesion molecules comprised of L-, E-, and P-selectin. Differences in expression patterns, protein structure, and ligand binding characteristics mediate distinct functions of each selectin. Interactions of selectins and their counter-receptors mediate the first contact of neutrophils with the endothelium, as well as subsequent neutrophil rolling along the endothelial surface. For efficient neutrophil recruitment, activation of β₂-integrins on the cell surface is essential. Integrin activation can be elicited via selectin- as well as chemokine-mediated inside-out signaling resulting in integrin conformational changes and clustering. Dysregulation of selectin-induced integrin activation on neutrophils is involved in the development of severe pathological disease conditions including leukocyte adhesion deficiency (LAD) syndromes in humans. Here, we review molecular mechanisms involved in selectin-mediated signaling pathways in neutrophils and their impact on integrin activation, neutrophil recruitment, and inflammatory diseases.

Keywords: PSGL-1; integrin; leukocyte recruitment; neutrophil; selectin; shedding; signaling.

Figure 1

β₂-integrins during neutrophil recruitment and transition from rolling to slow rolling. In case of tissue injury or infection, neutrophils are able to directionally extravasate in large numbers out of the bloodstream into the tissue. Activity regulation of β₂-integrins on the neutrophil surface is very important for different steps of the leukocyte recruitment cascade. Selectin-dependent integrin activation during neutrophil capturing and rolling mediates the activation of LFA-1, necessary for neutrophil slow rolling and subsequent recruitment. Key molecules involved in different recruitment steps are indicated below. ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte-function-associated antigen-1; Mac-1, macrophage antigen-1; PSGL-1, P-selectin glycoprotein ligand-1; VLA-4, very late antigen-4.

Figure 2

Selectin structure and expression. The selectin family consists of three members: E-selectin is expressed on the surface of activated endothelial cells, P-selectin occurs on endothelial cells as well as on platelets. L-selectin is expressed on leukocytes and can be shed by specific enzymes including A disintegrin and metalloproteinase 17 (ADAM17). Selectins share a common structure, characterized by an N-terminal C-type lectin domain, followed by an epidermal-growth-factor-like domain (EGF) and a number of consensus repeats, which is characteristic for each selectin. The transmembrane domain is followed by a short cytoplasmic tail. The cytoplasmic tail of L-selectin (amino acid sequence shown at the bottom) is highly conserved between species and is able to fulfill signaling function.

Figure 3

Inside-out signaling cascade in neutrophils induced by selectin–ligand binding. Selectin-binding to P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophil surface, elicits a specific intracellular signaling pathway resulting in affinity activation of lymphocyte-function-associated antigen-1 (LFA-1). Downstream of selectin-PSGL-1-ligation, several signaling molecules including kinases, adapter proteins, and GTPases are activated. The complex signaling machinery results in conformational changes of LFA-1 from a bent conformation with low ligand binding affinity to an extended conformation with intermediate ligand binding affinity. Extended LFA-1 is able to bind ICAM-1 on the endothelial surface, promoting the transition from neutrophil rolling to slow rolling.