Leukocyte extravasation is one of the essential and first steps during

Leukocyte extravasation is one of the essential and first steps during the initiation of inflammation. Peramivir subsets whereas other mechanisms are known only for a single leukocyte subset. Here we summarize current knowledge on regulatory mechanisms of leukocyte extravasation from a leukocyte and endothelial point of view respectively. Specifically we will focus on highlighting common and unique mechanisms that specific leukocyte subsets exploit to succeed in crossing endothelial monolayers. 1 Introduction The inflammatory response is critical for fighting infections and wound healing and is thus indispensable for survival [1 2 However continuously active immune responses precede chronic inflammatory disorders and other Tnf pathologies. Thus the immune response to injury and infection needs to be tightly controlled. In order to specifically interfere with excessive leukocyte transendothelial migration (TEM) a detailed understanding of the regulation of this multistep process is required. Butcher and Springer proposed in timeless reviews a multistep model for the process of TEM [3 4 Currently this proposed model is still valid; however over time some additional steps have been added to the sequence of events during TEM [2]. The inflammatory response starts with secretion of proinflammatory mediators such as histamine or cytokines that induce the opening of endothelial cell (EC) Peramivir contacts in postcapillary venules to allow for passage of blood molecules for example complement factors. Inflammation also involves surface expression of endothelial adhesion molecules actin remodeling and activation of leukocyte integrins that enable leukocyte adhesion onto the endothelium within the vascular wall and subsequent diapedesis [5-8]. The sequence of adhesive interactions of leukocytes with EC is termed leukocyte extravasation cascade and involves a series of adhesive interactions that allow first tethering rolling and slow rolling followed by firm adhesion crawling and transmigratory cup formation on the apical endothelial surface (Figure 1). Next is the actual TEM of leukocytes (also termed diapedesis) that can occur by crossing either EC contacts (paracellular) or the body Peramivir of EC (transcellular). Both ways exist and it is known that the strength of endothelial junctions controls route preference [9] but the exact underlying mechanisms remain elusive. After crossing the endothelium leukocytes also have to cross the pericyte layer and the basement membrane (BM) to reach the inflamed tissue and contribute to clearance of infection and wound healing [10]. Different types of leukocytes are being recruited to sites of inflammation including neutrophils monocytes and lymphocytes. In response to an inflammatory stimulus neutrophils are generally among the first leukocytes to exit the blood stream and after degranulation they contribute to a second wave of transmigration by mainly monocytes [11]. The reverse Peramivir case has also been observed in which the presence of monocytes and monocyte-derived neutrophil chemoattractants were required for neutrophil recruitment to sites of sterile inflammation [12]. Recruitment of all of these leukocyte subsets is compulsory for a proper immune response since all fulfill different functions once recruited to the inflamed tissue [13]. All these leukocyte types follow the sequential steps of the extravasation cascade in general but differences in responsiveness to certain chemokines and in expression/activation of adhesion molecules to mediate interactions with EC have been described [8 14 Several mechanisms during the leukocyte extravasation cascade such as certain Peramivir receptor-ligand interactions or signaling pathways have been confirmed as being exploited by all leukocyte subsets. However other mechanisms have so far only been described for a single type of leukocyte. Whether these mechanisms are indeed unique for a given leukocyte subset or whether it has just not been studied yet in other leukocyte subsets is an important question to be answered in the future. A plethora of reviews have been published that summarize several aspects of leukocyte recruitment but in a generalized form that speaks only of “leukocytes.” In this review we summarize current knowledge on common and unique mechanisms that different leukocyte types such as neutrophils monocytes and lymphocytes exploit during extravasation (Table 1). This includes.