Neutrophil-endothelial cell interactions: mechanisms of neutrophil adherence to vascular endothelium

Abstract

Adherence of circulating neutrophils to the microvascular endothelium is the initial step in diapedesis, the process by which leukocytes migrate through blood vessels to accumulate at sites of cutaneous disease or injury. The mechanisms underlying neutrophil-endothelial cell interactions are currently under intense investigation. It has now been clearly shown that human neutrophil adherence in vitro to cultured human endothelial cell monolayers can be enhanced by a variety of mediators of inflammation, that both the neutrophil and the endothelial cell may actively contribute to the adhesive interaction depending on the stimuli involved, and that the Mac-1, LFA-1, p150,95 glycoprotein family (CD11/CD18) plays a critical role. Chemotactic peptides (FMLP, C5a) and lipid mediators (LTB4, PAF) act primarily on the neutrophil to enhance its adherence to endothelium. The effect occurs quickly (maximal response within 2 min), can be rapidly modulated, and is dependent on the expression of CD11/CD18 on the neutrophil surface. In contrast, the cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), as well as bacterial lipopolysaccharide (LPS), induce cultured human endothelial cells to increase their adhesivity for human neutrophils by a process that is time-dependent, requiring 4 to 6 h for maximal response, and involves de novo RNA and protein synthesis. Two adhesion molecules are induced on the surface of endothelium in response to cytokine activation: endothelial-leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is a ligand for LFA-1 (CD11a/CD18). Thus, CD11/CD18 plays a central role in neutrophil adherence to endothelium stimulated by chemotactic factors or cytokines. However, much still remains to be explored to further understanding of the fascinating but complex interaction of circulating neutrophils and the microvascular endothelium during acute inflammatory reactions in the skin.