Abstract
Leukocyte recruitment to the inflammation site is a multi‐step process governed by specific signalling cascades. After adhesion in the lumen, leukocytes crawl to optimal sites at endothelial junctions and transmigrate to extravascular tissue in a Mac‐1‐dependent manner. The signalling mechanisms that regulate post‐adhesion steps of intraluminal crawling, transmigration and chemotaxis in tissue remain incompletely understood. The present study explored the effect of p38 MAPK inhibitor SB203580 on various steps of neutrophil recruitment triggered by chemokine KC (CXCL1) gradient in microvasculature of murine cremaster muscle using intravital microscopy and time‐lapsed video analysis. SB203580 (100 nM) did not change leukocyte rolling but significantly attenuated neutrophil adhesion, emigration, transmigration time and detachment time, and impaired the initiation of crawling and transmigration. In response to KC chemotactic gradient, SB203580 significantly reduced the velocity of migration and chemotaxis index of neutrophils in tissue. The upregulation of Mac‐1 expression in neutrophils stimulated by KC was significantly blunted by SB203580 in vitro. Collectively, our findings demonstrate that pharmacological suppression of p38 MAPK significantly impairs multiple steps of neutrophil recruitment in vivo.
Highlights
During acute inflammation, leukocytes, mostly neutrophils, are recruited to the afflicted site by a well-defined and dynamic multistep process which includes leukocyte tethering, rolling, adhesion, and transmigration out of the vasculature [1,2,3]
We demonstrate the effects of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on the modulation of different steps of neutrophil recruitment
We found that in vivo treatment with SB203580 does not appreciably alter the parameters of neutrophil intraluminal crawling but significantly modifies cellular functions during transendothelial migration and chemotaxis in tissue
Summary
Leukocytes, mostly neutrophils, are recruited to the afflicted site by a well-defined and dynamic multistep process which includes leukocyte tethering, rolling, adhesion, and transmigration out of the vasculature [1,2,3]. Neutrophil rolling is mediated by selectins, and adhesion is mediated by β2 integrins while emigration is regulated by the interactions between integrins, PECAM-1, and junctional adhesion molecules and their respective ligands [4]. An additional step of neutrophil recruitment termed intraluminal crawling was described, a process which is molecularly distinct from adhesion [5]. Intraluminal crawling enables neutrophils to reach optimal emigration sites at endothelial junctions independently of hemodynamic forces [6, 7]. The β2 integrin LFA-1 mediates firm adhesion of neutrophils to endothelial cells while the subsequent step of intraluminal crawling occurs as a result of interactions between Mac-1 and endothelial ICAM-1 [5]. Signalling mechanisms that regulate intraluminal crawling and subsequent transendothelial migration of leukocytes are not completely understood
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