Abstract
Leukocyte recruitment is a hallmark of the inflammatory response. Migrating leukocytes breach the endothelium along with the vascular basement membrane and associated pericytes. While much is known about leukocyte-endothelial cell interactions, the mechanisms and role of pericytes in extravasation are poorly understood and the classical paradigm of leukocyte recruitment in the microvasculature seldom adequately discusses the involvement of pericytes. Emerging evidence shows that pericytes are essential players in the regulation of leukocyte extravasation in addition to their functions in blood vessel formation and blood-brain barrier maintenance. Junctions between venular endothelial cells are closely aligned with extracellular matrix protein low expression regions (LERs) in the basement membrane, which in turn are aligned with gaps between pericytes. This forms preferential paths for leukocyte extravasation. Breaching of the layer formed by pericytes and the basement membrane entails remodelling of LERs, leukocyte-pericyte adhesion, crawling of leukocytes on pericyte processes, and enlargement of gaps between pericytes to form channels for migrating leukocytes. Furthermore, inflamed arteriolar and capillary pericytes induce chemotactic migration of leukocytes that exit postcapillary venules, and through direct pericyte-leukocyte contact, they induce efficient interstitial migration to enhance the immunosurveillance capacity of leukocytes. Given their role as regulators of leukocyte extravasation, proper pericyte function is imperative in inflammatory disease contexts such as diabetic retinopathy and sepsis. This review summarizes research on the molecular mechanisms by which pericytes mediate leukocyte diapedesis in inflamed tissues.
Highlights
Recruitment of leukocytes to sites of infection or injury is a tightly regulated multistep process controlled by leukocyte interactions with the endothelial layer and the ability of the leukocyte to breach the vascular wall
These transient adhesive interactions are mediated by endothelial P-selectin/CD62P and E-selectin/CD62E binding to leukocyte glycoprotein ligands such as P-selectin glycoprotein ligand- (PSGL-) 1/CD162 and E-selectin ligand- (ESL-) 1
Damage-Associated Molecular Patterns (DAMPs) and Pathogen-Associated Molecular Patterns (PAMPs) trigger the expression of adhesion molecules and chemokines on the surface of endothelial cells, which promotes neutrophil migration to sites of tissue damage or infection [33]
Summary
Recruitment of leukocytes to sites of infection or injury is a tightly regulated multistep process controlled by leukocyte interactions with the endothelial layer and the ability of the leukocyte to breach the vascular wall. The rolling leukocyte stops as it adheres to endothelial cells, an interaction mediated by adhesion molecules expressed on the endothelium, such as intercellular adhesion molecule(ICAM-) 1/CD54 and vascular cell adhesion molecule(VCAM-) 1/CD106. These molecules interact with leukocyte β2 (lymphocyte function-associated antigen- (LFA-) 1; CD11a/CD18) and α4 integrins, respectively [8]. Leukocytes may crawl for variable distances on the endothelium via ICAM-1 and macrophage-1 antigen (Mac-1; CD11b/CD18)dependent mechanism [9] This step is followed by leukocyte breaching of the endothelial layer, which mostly happens in a paracellular fashion. This review will further describe specific cellular and molecular mechanisms of these leukocyte-pericyte interactions with an emphasis on murine neutrophils and monocytes—the cells that are the focus of most studies on this topic
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