Four-and-a-Half LIM Domain Protein 2 Is a Novel Regulator of Sphingosine 1-Phosphate Receptor 1 in CCL19-Induced Dendritic Cell Migration

König, Katharina; Diehl, Linda; Rommerscheidt-Fuss, Ursula; Golletz, Carsten; Quast, Thomas; Kahl, Philip; Kolanus, Waldemar; Knolle, Percy A.; Buettner, Reinhard; Heukamp, Lukas C.

doi:10.4049/jimmunol.0903449

Cited by 33 publications

(32 citation statements)

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“…23 Moreover, another recent study showed that FHL2 is an important regulator of chemotactic dendritic cell migration. 34 Integrins play a key role in cell motility, and we found a significant increase in αv/β5 and αv/β3 subunit expression in human EOCs after FHL2 knockdown. In contrast, active β1 and β2 subunits were unchanged.…”

Section: Discussionmentioning

confidence: 63%

“…23 Moreover, regulation of dendritic cell migration by FHL2 involves activation of S1PR-1. 34 Therefore, we hypothesized that FHL2 inhibition in EOCs could activate the SK-1/S1P system, leading to the activation of prosurvival and promigratory pathways. We observed less apoptosis and enhanced SDF-1-induced migration in EOCs stimulated with exogenous S1P.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Ebrahimian

Arfa

Simeone

et al. 2014

Circulation Research

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Rationale: Inhibition of four-and-a-half LIM domain protein-2 (FHL2) attenuates atherosclerotic lesion formation and increases endothelial cell migration. Early outgrowth cells (EOCs) contribute substantially to endothelial repair. Objective: We investigated the role of FHL2 in the regulation of EOCs. Methods and Results: Human EOCs were cultured from peripheral blood. FHL2 knockdown in EOCs by siRNA resulted in increased EOC numbers and reduced apoptosis, as indicated by decreased cleaved caspase-III and reduced Bax/Bcl-2 expression ratio. This was mediated through increased phosphorylation and membrane translocation of sphingosine kinase-1, increased sphingosine-1-phosphate levels, and Akt phosphorylation. FHL2 knockdown increased stromal cell–derived factor-1–induced EOC migration through upregulation of αv/β3, αv/β5, and β2 integrins, associated with increased cortactin expression. Reduced apoptosis, increased EOC migration, and cortactin upregulation by FHL2 siRNA were prevented by CAY10621, the sphingosine kinase-1 inhibitor, and the sphingosine-1-phosphate receptor-1/-3 antagonist VPC23019. These findings were confirmed using spleen-derived EOCs from FHL2 −/− mice. Apoptosis was decreased and migration increased in endothelial cells exposed to the conditioned medium of FHL2 −/− versus wild-type (WT) EOCs. These paracrine effects were abolished by VPC23019. Importantly, reendothelialization after focal carotid endothelial injury in WT mice was significantly increased after intravenous injection of FHL2 −/− versus WT EOCs. Conclusions: Our findings suggest that FHL2 negatively regulates EOC survival, migration, and paracrine function. FHL2 inhibition in EOCs reduces apoptosis and enhances survival and migratory capacity of both EOCs and surrounding endothelial cells by activation of the sphingosine kinase-1/sphingosine-1-phosphate pathway, resulting in improvement of endothelial regeneration.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Ebrahimian

Arfa

Simeone

et al. 2014

Circulation Research

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“…Sphingosine kinase participates in several instances of vertebrate cell migration (24). lim-9's mammalian ortholog FHL2 inhibits sphingosine kinase (25) and is involved in colon cancer invasion (26) and dendritic cell migration (27).…”

mentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

Proc. Natl. Acad. Sci. U.S.A.

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In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25% of which were up-or downregulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.major sperm protein | nematode development | transcriptional profiling | twin pore potassium channels | conserved uncharacterized proteins C ell migration is pervasive in animal development and is also an unwanted part of human cancer. Several different varieties of cell migration, ranging from social protozoa to the human immune system, have been extensively studied (1), but there remains a need for detailed analysis of the different components of migration in a simple cell type that can be exhaustively probed through anatomy, genetics, and genomics. We have undertaken to develop the linker cell (LC) of Caenorhabditis elegans as such a model. The LC is a single cell, attached to the front of a proliferating male gonad, which carries out a stereotypic, long-range migration to generate the shape of the mature gonad (Fig. 1A). During 25 h of the second to fourth larval stages (L2 through L4), the LC moves anteriorly along the ventral body wall, turns dorsally, proceeds posteriorly, switches sides once more to the ventral bodywall, continues posteriorward, reaches the cloaca, and eventually dies (2-4). Throughout this process, the proliferating and lengthening male gonad follows the LC's path to the cloaca. Stage-specific changes occur during the middle to late stages of migration (L3 and L4 larval stages): the LC changes shape from a spheroid to a pointed ellipsoid; it increases its speed of migration; and the netrin receptor gene unc-5 is down-regulated within the LC, which causes it to switch body walls ventrally ( Fig. 1A; ref. 3). These changes between the L3 and L4 stages require the orphan nuclear receptor NHR-67, whose orthologs TAILLESS and TLX...

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“…18 In the present study, we demonstrate that the absence of FHL2 in myeloid and vascular cells reduces plaque development in the ApoE −/− atherosclerotic mouse model. Moreover, we provide evidence that this atheroprotective effect could be, at least in part, because of reduced adhesion molecule expression in endothelial cells and because of a change in the chemokine/chemokine receptor expression balance leading to decreased recruitment of 20 and macrophages. 24 We verified that FHL2 is indeed highly expressed in the atherosclerotic plaque of ApoE −/− mice.…”

Section: Discussionmentioning

confidence: 84%

“…18 FHL2 deletion also increased dendritic cell migratory speed, persistence, and directionality, 19,20 whereas it reduced macrophage activation and expression of inflammatory cytokines interleukin-6 and tumor necrosis factor-α. 21 In summary, FHL2 has been shown to influence many cell types associated with atherosclerosis.…”

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confidence: 95%

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice

Ebrahimian

Simon

Lemarié

et al. 2015

ATVB

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A therosclerosis is a chronic inflammatory disease that is characterized by modifications in the vascular, metabolic, and immune systems. The accumulation of leukocytes within atherosclerotic lesions is a process regulated at various levels, including mobilization, recruitment, and endothelial adhesion of monocytes, followed by their migration into the intima and differentiation into macrophages.1,2 Two major monocyte subsets can be distinguished in the blood based on differential expression of the chemokine receptors CCR2 and CX 3 CR1. The inflammatory monocytes express high levels of CCR2 but low levels of CX 3 CR1, whereas the patrolling monocytes have low levels of CCR2 and high levels of CX 3 CR1.3,4 Inflammatory monocytes rapidly enter the atherosclerotic plaque where they give rise to macrophages. As macrophages accumulate in the atherosclerotic lesion, they incorporate lipids and become foam cells, eventually forming necrotic cores that fragilize the plaque. The inflammatory milieu attracts diverse immune cells but also promotes vascular smooth muscle cell (VSMC) infiltration from the media. Accumulation of VSMCs and collagen synthesis by these cells is associated with a reduced risk of rupture. 5Four-and-a-half LIM domain protein 2 (FHL2, SLIM3) is the best-studied member of the LIM-only subclass of the LIM protein superfamily. LIM proteins are defined by the presence of ≥1 LIM domains composed of a conserved cysteine-rich module that mediates protein-protein interactions. 6 Multiple roles have been ascribed to FHL2. FHL2 exerts its function as a transcriptional cofactor, interacting with a broad range of transcription factors, and modulating the transcription of many proteins such as the androgen receptor, cAMP response element-binding protein, integrins, β-catenin, presenilin-2, ERK-2 (extracellular signal-regulated kinase), AP-1, and sphingosine kinase-1. [7][8][9][10][11][12] It modulates cellular processes such as cell survival, proliferation, and signal transduction.13 FHL2© 2015 American Heart Association, Inc.

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Four-and-a-Half LIM Domain Protein 2 Is a Novel Regulator of Sphingosine 1-Phosphate Receptor 1 in CCL19-Induced Dendritic Cell Migration

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/06/30/jimmunol.090344

Cited by 33 publications

References 58 publications

Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice

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Four-and-a-Half LIM Domain Protein 2 Is a Novel Regulator of Sphingosine 1-Phosphate Receptor 1 in CCL19-Induced Dendritic Cell Migration

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/06/30/jimmunol.090344

Cited by 33 publications

References 58 publications

Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE −/− Mice

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Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice