Blockade of α6 integrin inhibits IL-1β- but not TNF-α-induced neutrophil transmigration in vivo

Dangerfield, John A.; Wang, Shijun; Nourshargh, Sussan

doi:10.1189/jlb.0704421

Cited by 52 publications

(42 citation statements)

References 33 publications

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“…Surprisingly, our results show that the directionality of chemotaxing neutrophils toward CXCL2 gradient was affected in mice with endothelial cell-specific deficiency of LSP1 in contrast to previous reports showing that neutrophil chemotaxis toward KC/CXCL1 gradient was neutrophil LSP1 dependent (23). It is documented that the inhibitory effect of a 6 blocking on neutrophil recruitment is chemoattractant specific and involves reduced transendothelial migration, and the impact of a 6 blocking on extravascular chemotaxis was not determined (29,30,43). However, our in vitro and in vivo results demonstrate that functionally blocking a 6 did not affect the speed of neutrophil migration but impaired the directionality, an observation that has not been reported previously.…”

Section: Discussioncontrasting

confidence: 53%

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Hossain

Qadri

et al. 2015

The Journal of Immunology

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During inflammation, leukocyte–endothelial cell interactions generate molecular signals that regulate cell functions. The Ca2+- and F-actin–binding leukocyte-specific protein 1 (LSP1) expressed in leukocytes and nonhematopoietic endothelial cells is pivotal in regulating microvascular permeability and leukocyte recruitment. However, cell-specific function of LSP1 during leukocyte recruitment remains elusive. Using intravital microscopy of cremasteric microvasculature of chimeric LSP1-deficient mice, we show that not neutrophil but endothelial LSP1 regulates neutrophil transendothelial migration and extravascular directionality without affecting the speed of neutrophil migration in tissue in response to CXCL2 chemokine gradient. The expression of PECAM-1–sensitive α6β1 integrins on the surface of transmigrated neutrophils was blunted in mice deficient in endothelial LSP1. Functional blocking studies in vivo and in vitro elucidated that α6β1 integrins orchestrated extravascular directionality but not the speed of neutrophil migration. In LSP1-deficient mice, PECAM-1 expression was reduced in endothelial cells, but not in neutrophils. Similarly, LSP1-targeted small interfering RNA silencing in murine endothelial cells mitigated mRNA and protein expression of PECAM-1, but not ICAM-1 or VCAM-1. Overexpression of LSP1 in endothelial cells upregulated PECAM-1 expression. Furthermore, the expression of transcription factor GATA-2 that regulates endothelial PECAM-1 expression was blunted in LSP1-deficient or LSP1-silenced endothelial cells. The present study unravels endothelial LSP1 as a novel cell-specific regulator of integrin α6β1-dependent neutrophil extravascular chemotactic function in vivo, effective through GATA-2–dependent transcriptional regulation of endothelial PECAM-1 expression.

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Section: Discussioncontrasting

confidence: 53%

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Hossain

Qadri

et al. 2015

The Journal of Immunology

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“…Such modulation has been described, for instance, for CD31/PECAM-1 receptor, shown to regulate both cell adhesive and migratory functions of ␣4 or ␣6 integrins in hematopoietic cells. 37,38,47 Integrin ␣4 chain may assemble with ␤1 or ␤7 chain to form receptors for ECM protein fibronectin and endothelial counterreceptors VCAM-1 and MAdCAM. 40 Integrin ␣6 chain can be assembled with either ␤1 or ␤4 chain to form receptors mainly for laminins.…”

Section: Discussionmentioning

confidence: 99%

“…The antiintegrin ␣6 antibody GoH3 used has been shown to be functionally active in vivo by inhibiting transendothelial migration of neutrophils. 37,38 BM cells were incubated with the anti-integrin or control antibodies and injected intravenously into recipient mice. It has been shown previously that most stem and progenitor cells that home into BM transmigrate rapidly after injection into blood.…”

Section: Integrin ␣6 Mediates Cfu-gm Homing To Bm But Not To Spleenmentioning

confidence: 99%

Contribution of α6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with α4 integrins

Qian

Tryggvason

Jacobsen

et al. 2006

Blood

119

108

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The laminin receptor integrin ␣6 chain is ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells. We have studied its role for homing of stem and progenitor cells to mouse hematopoietic tissues in vivo. A function-blocking anti-integrin ␣6 antibody significantly reduced progenitor cell homing to bone marrow (BM) of lethally irradiated mice, with a corresponding retention of progenitors in blood. Remarkably, the anti-integrin ␣6 antibody profoundly inhibited BM homing of long-term multilineage engrafting stem cells, studied by competitive repopulation assay and analysis of donor-derived lymphocytes and myeloid cells in blood 16 weeks after transplantation. A similar profound inhibition of long-term stem cell homing was obtained by using a function-blocking antibody against ␣4 integrin, studied in parallel. Furthermore, the anti-integrin ␣6 and ␣4 antibodies synergistically inhibited homing of short-term repopulating stem cells. Intravenous injection of antiintegrin ␣6 antibodies, in contrast to antibodies against ␣4 integrin, did not mobilize progenitors or enhance cytokineinduced mobilization by G-CSF. Our results provide the first evidence for a distinct functional role of integrin ␣6 receptor during hematopoietic stem and progenitor cell homing and collaboration of ␣6 integrin with ␣4 integrin receptors during homing of short-term stem cells. IntroductionHematopoietic stem cell (HSC) properties, like self-renewal, proliferation, differentiation, and migration are critically dependent on the regulatory signals from the surrounding bone marrow (BM) microenvironment. Cytokines, growth factors, stromal cell surface molecules, and extracellular matrix (ECM) molecules contribute to this regulation by binding to distinct cell surface receptors and thereby activating intracellular signal transduction pathways. During steady-state hematopoiesis, small numbers of HSCs are circulating in blood, indicating that their continuous mobilization into blood and homing into BM is a physiologic process. 1 For clinical stem cell transplantation, HSCs are mobilized from BM by injection of growth factors and can be harvested from blood. After transplantation, HSCs selectively transmigrate through the sinusoidal walls into the BM extravascular spaces to engraft and reconstitute hematopoiesis. In leukemias, cell proliferation, differentiation, and migration are dysregulated, and consequently high numbers of immature malignant cells are released into blood and accumulate in the BM, and aberrantly in other tissues.The molecular mechanisms involved in HSC homing and mobilization have been widely studied, but are still not fully understood. 2,3 They are apparently multistep processes involving chemokines, growth factors, matrix-degrading enzymes, and cell adhesive interactions mediated by specific receptors on hematopoietic cells. Members of the integrin family of adhesion receptors are widely expressed in the hematopoietic system, and both in vitro and in vivo studies have indicated decisive roles for several ...

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“…To circumvent this possibility of compensation, we also used a function-blocking antibody to evaluate the effect of a more immediate loss of integrin ␣6 function for progenitor cell homing. The anti-integrin ␣6 antibody GoH3 used has previously been shown to inhibit transendothelial migration of neutrophils in vivo 49,50 and homing of adult mouse HPCs and HSCs to BM vivo. 19 FL cells were preincubated with the anti-integrin or control antibodies and injected intravenously into lethally irradiated recipient mice.…”

Section: Integrin ␣6 Antibody Inhibits Fl Hpc Homing To Bm and Spleenmentioning

confidence: 99%

Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cells

Qian

Georges-Labouesse

Nyström

et al. 2007

Blood

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Homing of hematopoietic stem cells (HSCs) into the bone marrow (BM) is a prerequisite for establishment of hematopoiesis during development and following transplantation. However, the molecular interactions that control homing of HSCs, in particular, of fetal HSCs, are not well understood. Herein, we studied the role of the ␣6 and ␣4 integrin receptors for homing and engraftment of fetal liver (FL) HSCs and hematopoietic progenitor cells (HPCs) to adult BM by using integrin IntroductionDuring transplantation, intravenously injected hematopoietic stem and progenitor cells (HSPCs) selectively transmigrate through the sinusoidal walls into the bone marrow (BM) niches to engraft and reconstitute hematopoiesis. This process, called homing, is a rapid multistep process involving multiple adhesion receptor and ligand pairs, leading first to reversible adhesion of circulating HSPCs to endothelial cells of BM sinusoids and subsequently transmigration through the sinusoidal walls into the specific hematopoietic niches. 1 The adhesive interactions mediated by distinct receptors on hematopoietic cells regulate the localization, migration, and other HSPC functions within their native microenvironments, and are likely to define their homing potential in a transplantation setting. 2 The rate of reconstitution following transplantation varies depending on the source of hematopoietic stem cells (HSCs), suggesting developmentally regulated and cell type-specific differences in expression and function of homing receptors. Cord blood grafts are associated with a particularly delayed hematopoietic reconstitution. 3 In contrast, experimental studies have shown a more rapid and robust reconstitution of both human and mouse fetal liver (FL) HSCs than adult BM HSCs. 4,5 Increasing HSC homing and engraftment efficiency might offer a means to enhance reconstitution, which may be critically important if donor cell numbers are limiting, as frequently observed in cord blood units. 3 Therefore, knowledge of the specific molecular mechanisms involved in homing and engraftment of different types of HSPCs is of clinical significance for the development of clinical transplantation methods.Mouse models for mammalian hematopoiesis are widely used to study developmentally regulated HSC functions, including mobilization, homing, and engraftment. 6 During mammalian ontogeny, HSCs develop sequentially in distinct hematopoietic tissues, beginning in the yolk sac and subsequently in the aorta-gonadmesonephros region in the embryo proper. At embryonic day 10 (E10) in mice, definitive hematopoiesis arises in the liver, which is the main site of hematopoiesis throughout subsequent fetal development. 7 In later gestation, hematopoiesis expands into spleen (E15) and thereafter into BM (E17). This shift in hematopoiesis is accomplished by migration of liver HSPCs into spleen and BM, and consequently, is associated with mobilization of large numbers of HSPCs into the bloodstream. 6 Despite the central role of migration and homing in stem-cell biology and in st...

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Blockade of α6 integrin inhibits IL-1β- but not TNF-α-induced neutrophil transmigration in vivo

Cited by 52 publications

References 33 publications

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Contribution of α6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with α4 integrins

Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cells

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