Regulation of L-Selectin Expression by Membrane Proximal Proteolysis

Tk, Kishimoto; Kahn, Julius; G, Migaki; Mainolfi, Elizabeth; Shirley, Francine; Ingraham, Richard H.; Rothlein, Robert

doi:10.1007/978-3-0348-7343-7_11

Cited by 17 publications

(25 citation statements)

References 31 publications

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“…10,11 The role of ADAM17 in homeostatic L-selectin shedding was assessed by comparing the levels of plasma L-selectin from ADAM17 ⌬Zn/⌬Zn -chimeric mice and control mice. Remarkably, plasma L-selectin levels for the ADAM17 ⌬Zn/⌬Zn -and ADAM17 ϩ/ϩ -chimeric mice were found not to be significantly different (0.47 Ϯ 0.12 g/mL and 0.51 Ϯ 0.17 g/mL, respectively [SD; n ϭ 4 for each group of chimeric mice]).…”

Section: Adam17 Deficiency Does Not Alter L-selectin Shedding Upon Spmentioning

confidence: 99%

“…Studies involving gene-targeted mice expressing noncleavable L-selectin indicate that ectodomain shedding regulates surface L-selectin density, and this affects the efficiency of leukocyte adhesion and migration. 20 Homeostatic L-selectin cleavage accounts for high levels of the receptor in the plasma of healthy individuals and mice relative to other leukocyte membrane proteins, 10,11 and perhaps this process maintains an adhesion buffer.…”

Section: Introductionmentioning

confidence: 99%

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ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding

Liu

Brazzell

Herrera

et al. 2006

Blood

104

119

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L-selectin directs neutrophils to sites of inflammation, and upon their activation, surface expression of the receptor is rapidly down-regulated by ectodomain shedding. Tumor necrosis factor-␣-converting enzyme (TACE, or ADAM17) is a sheddase of L-selectin; however, Adam17 gene targeting (ADAM17 ⌬Zn/⌬Zn ) in mice is perinatal lethal and its role in L-selectin shedding by mature neutrophils has not been determined. This was addressed here by using radiation-chimeric mice reconstituted with ADAM17 ⌬Zn/⌬Zn fetal liver cells. ADAM17-deficient neutrophils, monocytes, and lymphocytes failed to shed L-selectin in response to PMA, as did neutrophils infiltrating the inflamed peritoneum. In addition, the absence of functional ADAM17 resulted in significantly increased levels of L-selectin surface expression by peripheral-blood leukocytes, indicating the sheddase also plays a role in the constitutive cleavage of L-selectin. Interestingly, not all manners of L-selectin turnover required ADAM17. Plasma L-selectin levels were similar between ADAM17 ⌬Zn/⌬Zn -chimeric and control mice, as was the shedding of L-selectin by neutrophils undergoing spontaneous apoptosis. The latter process, however, was diminished by a metalloprotease inhibitor, indicating the role of a sheddase other than ADAM17. Together, our data reveal that L-selectin's surface density on neutrophils is regulated by ADAM17, but homeostatic L-selectin cleavage is not. IntroductionL-selectin (CD62L) is a type-1 transmembrane protein that is constitutively and uniformly expressed by neutrophils. It plays a critical role in directing these cells to sites of inflammation. L-selectin's adhesive role is diverse and includes facilitating direct and indirect neutrophil tethering along the vascular wall. 1 The latter process both accelerates and prolongs their accumulation. [2][3][4][5] Consistent with L-selectin's broad role in directing leukocyte accumulation, it is tightly regulated. This includes a rapid and efficient down-regulation from the surface of neutrophils upon their activation by various stimuli, with virtually all of the L-selectin molecules being released by a proteolytic process. 6 In addition to neutrophil activation, L-selectin shedding also occurs by these cells upon induced and spontaneous apoptosis. 7 The cleavage of L-selectin takes place proximal to the cell membrane, releasing an intact ectodomain fragment. 8,9 The soluble ectodomain portion of L-selectin is detected in the blood plasma, demonstrating that L-selectin shedding is a physiologic process. The functional relevance of L-selectin shedding is not yet fully understood. Studies involving gene-targeted mice expressing noncleavable L-selectin indicate that ectodomain shedding regulates surface L-selectin density, and this affects the efficiency of leukocyte adhesion and migration. 20 Homeostatic L-selectin cleavage accounts for high levels of the receptor in the plasma of healthy individuals and mice relative to other leukocyte membrane proteins, 10,11 and perhaps this process maintains an...

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Section: Adam17 Deficiency Does Not Alter L-selectin Shedding Upon Spmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding

Liu

Brazzell

Herrera

et al. 2006

Blood

104

119

View full text Add to dashboard Cite

show abstract

“…The samples were stored at -80°C until analysis. A sandwich enzyme-linked immunosorbent assay technique for sL-selectin assessment was used (R&D Systems, Abingdon, UK) [9]. Briefly, 100 µl 1:100 diluted serum was preincubated with a specific monoclonal sL-selectin antibody, followed by addition of polyclonal antibodies conjugated with horseradish peroxidase.…”

Section: Study Design and Patientsmentioning

confidence: 99%

“…L-selectin is involved in the early binding and rolling of leukocytes on endothelial cells [8]. Upon chemokine activation of the leukocytes L-selectin is shed by specific proteolysis, and the extracellular part is released as soluble sL-selectin [8,9,10]. The function of L-selectin could therefore be crucial for the accumulation of leukocytes in tissues during sepsis, thus reflecting the level of MODS in these patients [11].…”

Section: Introductionmentioning

confidence: 99%

Soluble L-selectin levels predict survival in sepsis

Seidelin

Nielsen

Strøm

2002

Intensive Care Medicine

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“…The change in PMN adhesive profile from selectin to integrin expression is normally thought to occur at the vessel wall in response to endothelium-derived signals, yet circulating PMNs are identified with this profile during endotoxemia [9,13,90]. If the sequence of cell activation in PMNs is critical for transendothelial migration, an ''untimely'' mobilization of adhesion molecules on circulating PMNs in [130,131]. Although LPS can up-regulate peptidase activity on the PMN surface, similar up-regulation of metalloprotease activity has not been reported [132].…”

Section: Adhesionmentioning

confidence: 99%

Neutrophil migration during endotoxemia

Wagner

Roth

1999

Journal of Leukocyte Biology

177

125

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Endotoxemia is marked by a global activation of inflammatory responses, which can lead to shock, multiple organ failure, and the suppression of immune and wound healing processes. Neutrophils (PMNs) play a central role in some of these responses by accumulating in tissues and releasing reactive oxygen species and proteases that injure host structures. This review focuses on altered PMN migratory responses that occur during endotoxemia and their consequences in the development of pulmonary infection. The inflammatory mediators that might be responsible for these altered responses are discussed. The oxidant potential of PMNs is increased after exposure to endotoxin both in vitro and during clinical and experimental endotoxemia. However, other functions such as chemotaxis and phagocytosis are often depressed in these same cells. Endotoxin exposure renders PMNs hyperadhesive to endothelium. The sum of these effects produces activated inflammatory cells that are incapable of leaving the vasculature. As such, the endotoxic PMN is more likely to promote tissue injury from within microvascular beds than to clear pathogens from extravascular sites. Moreover, the functional characteristics of endotoxic PMNs are similar to those observed during trauma, burn injury, sepsis, surgery, and other inflammatory conditions. Accordingly, several clinical conditions might have a common effector in the activated, yet migratorially dysfunctional, PMN. Direct effects of endotoxin on PMNs as well as effects of endogenous mediators released during endotoxemia are discussed. Understanding PMN behavior during endotoxemia may provide basic and critical insights that can be applied to a number of inflammatory scenarios. J. Leukoc. Biol. 66: 10-24; 1999.

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Regulation of L-Selectin Expression by Membrane Proximal Proteolysis

Cited by 17 publications

References 31 publications

ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding

ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding

Soluble L-selectin levels predict survival in sepsis

Neutrophil migration during endotoxemia

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