RhoA activation promotes transendothelial migration of monocytes via ROCK

Honing, Henk; Berg, Timo K. van den; Pol, Susanne M. A. van der; Dijkstra, Christine D.; Kammen, Rob A. van der; Collard, John G.; Vries, Helga E. de

doi:10.1189/jlb.0203054

Cited by 87 publications

(79 citation statements)

References 25 publications

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“…2G). Consistent with previous knowledge on the positive role of RHOA in leukocyte adhesion to endothelium (Francis et al, 2006;Giagulli et al, 2004;Honing et al, 2004;Xu et al, 2010), we observed that enhanced adhesion of FAM65B-deficienct neutrophils to endothelial cells under flow (Fig. 2H).…”

Section: Resultssupporting

confidence: 81%

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Gao

Tang

et al. 2015

Journal of Cell Science

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A hallmark of neutrophil polarization is the back localization of active RHOA and phosphorylated myosin light chain (pMLC, also known as MYL2). However, the mechanism for the polarization is not entirely clear. Here, we show that FAM65B, a newly identified RHOA inhibitor, is important for the polarization. When FAM65B is phosphorylated, it binds to 14-3-3 family proteins and becomes more stable. In neutrophils, chemoattractants stimulate FAM65B phosphorylation largely depending on the signals from the front of the cells that include those mediated by phospholipase Cb (PLCb) and phosphoinositide 3-kinase c (PI3Kc), leading to FAM65B accumulation at the leading edge. Concordantly, FAM65B deficiency in neutrophils resulted in an increase in RHOA activity and localization of pMLC to the front of cells, as well as defects in chemotaxis directionality and adhesion to endothelial cells under flow. These data together elucidate a mechanism for RHOA and pMLC polarization in stimulated neutrophils through direct inhibition of RHOA by FAM65B at the leading edge.

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Section: Resultssupporting

confidence: 81%

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Gao

Tang

et al. 2015

Journal of Cell Science

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“…According to Carman et al, endothelial membranes positive for caveolin-1 are associated with the transmigrating leukocyte in the transmigration cup, which is dependent on the presence of lipid rafts and their recruitment of CAMs [74,100]. In this context, lipid rafts are believed to coordinate outside-in signaling in ECs and regulation of actin remodeling by lipid raft-associated small guanosine triphosphatases, such as Rho [104][105][106] and Rac [107,108], myosin-dependent contractions [109], and junctional protein regulation [8,110]. These transendothelial migration events are highly organized around CAMmediated signaling within lipid raft structures and support the concept of functionally distinct endothelial adhesion rafts.…”

Section: Adhesion Raftsmentioning

confidence: 99%

Functions of lipid raft membrane microdomains at the blood–brain barrier

et al. 2009

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The blood-brain barrier (BBB) is a highly specialized structural and functional component of the central nervous system that separates the circulating blood from the brain and spinal cord parenchyma. Brain endothelial cells (BECs) that primarily constitute the BBB are tightly interconnected by multiprotein complexes, the adherens junctions and the tight junctions, thereby creating a highly restrictive cellular barrier. Lipid-enriched membrane microdomain compartmentalization is an inherent property of BECs and allows for the apicobasal polarity of brain endothelium, temporal and spatial coordination of cell signaling events, and actin remodeling. In this manuscript, we review the role of membrane microdomains, in particular lipid rafts, in the BBB under physiological conditions and during leukocyte transmigration/diapedesis. Furthermore, we propose a classification of endothelial membrane microdomains based on their function, or at least on the function ascribed to the molecules included in such heterogeneous rafts: (1) rafts associated with interendothelial junctions and adhesion of BECs to basal lamina (scaffolding rafts); (2) rafts involved in immune cell adhesion and migration across brain endothelium (adhesion rafts); (3) rafts associated with transendothelial transport of nutrients and ions (transporter rafts).

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“…42,43 The Rho GTPases Rac, Cdc42, and Rho play an important role in the regulation of actin organization in cell motility and movement. In microglia, MCP-1 rapidly induced the activation of Rac, Cdc42, and Rho proteins, which were inhibited by LJ529 (Figure 4, A-C).…”

Section: Lj529 Disturbs Mcp-1-induced Spatial Localization Of Rho Gtpmentioning

confidence: 99%

A3 Adenosine Receptor Agonist Reduces Brain Ischemic Injury and Inhibits Inflammatory Cell Migration in Rats

Choi

Lee

et al. 2011

The American Journal of Pathology

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A3 adenosine receptor (A3AR) is recognized as a novel therapeutic target for ischemic injury; however, the mechanism underlying anti-ischemic protection by the A3AR agonist remains unclear. Here, we report that 2-chloro-N 6 -(3-iodobenzyl)-5=-N-methylcarbamoyl-4=-thioadenosine (LJ529), a selective A3AR agonist, reduces inflammatory responses that may contribute to ischemic cerebral injury. Postischemic treatment with LJ529 markedly reduced cerebral ischemic injury caused by 1.5-hour middle cerebral artery occlusion, followed by 24-hour reperfusion in rats. This effect was abolished by the simultaneous administration of the A3AR antagonist MRS1523, but not the A2AAR antagonist SCH58261. LJ529 prevented the infiltration/migration of microglia and monocytes occurring after middle cerebral artery occlusion and reperfusion, and also after injection of lipopolysaccharides into the corpus callosum. The reduced migration of microglia by LJ529 could be related with direct inhibition of chemotaxis and down-regulation of spatiotemporal expression of Rho GTPases (including Rac, Cdc42, and Rho), rather than by biologically relevant inhibition of inflammatory cytokine/chemokine release ( Excitotoxicity, peri-infarct depolarization, oxidative stress, apoptosis, and inflammation contribute to the development of cerebral injury after ischemia.1 To develop effective therapeutic strategies for postischemic brain injury, it is crucial to understand the highly diverse temporal profiles (eg, onset and duration) of these individual factors and to interrupt their pathophysiological cascades. The N-methyl-D-aspartate (NMDA) receptor blocker MK-801 markedly reduces ischemic brain injury; however, MK-801 has a brief therapeutic time window: the neuroprotective effect of MK-801 is obtained only when therapy is given within at most 1 hour after the onset of focal ischemia in rats and gerbils.2,3 Furthermore, MK-801 only postpones postischemic neuronal death; it does not improve either neurological recovery or endpoint cell survival at weeks after treatment. 4,5 Similarly, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists also did not significantly protect neuronal loss at 28 days after middle cerebral artery occlusion (MCAO).6 This short therapeutic window and lack of long-term effect of NMDA or AMPA receptor antagonists suggests that these receptors play only a transient role in the early ischemic cascade. Thus, some pathophysiological

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RhoA activation promotes transendothelial migration of monocytes via ROCK

Cited by 87 publications

References 25 publications

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Functions of lipid raft membrane microdomains at the blood–brain barrier

A3 Adenosine Receptor Agonist Reduces Brain Ischemic Injury and Inhibits Inflammatory Cell Migration in Rats

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