Publications by authors named "Lindsey A Miles"

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRS (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal metastatic disease associated with robust activation of the coagulation and fibrinolytic systems. However, the potential contribution of the primary fibrinolytic protease plasminogen to PDAC disease progression has remained largely undefined. Mice bearing C57Bl/6-derived KPC (KRas , TRP53 ) tumors displayed evidence of plasmin activity in the form of high plasmin-antiplasmin complexes and high plasmin generation potential relative to mice without tumors.

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The plasminogen receptor, Plg-R is a unique cell surface receptor that is broadly expressed in cells and tissues throughout the body. Plg-R localizes plasminogen on cell surfaces and promotes its activation to the broad-spectrum serine protease, plasmin. In this study, we show that overexpression of Plg-R protects mice from high fat diet (HFD)-induced adipose and metabolic dysfunction.

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The plasminogen/plasmin (Plg/Pla) system, best known for its classical role in thrombolysis, has been recently highlighted as a regulator of other biological processes in mammals, including key steps involved in the resolution of inflammation. Inflammation resolution is a complex process coordinated by different cellular effectors, notably leukocytes, and active mediators, and is initiated shortly after the inflammatory response begins. Once the inflammatory insult is eliminated, an effective and timely engagement of proresolution programs prevents persistent inflammation, thereby avoiding excessive tissue damage, fibrosis, and the development of autoimmunity.

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Article Synopsis
  • * A study found that lower levels of plasminogen (Plg) are linked with more severe sepsis, while higher levels of IL-6, a sepsis severity marker, are observed; there’s a negative correlation between Plg and IL-6 in both mice and humans.
  • * Deficiency of Plg made mice more vulnerable to less severe forms of sepsis, leading to more severe inflammation and organ damage, while introducing plasminogen or its active form improves survival and reduces inflammation-related damage.
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The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface.

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Background: Plg-R , a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface.

Objectives: We investigated the role of Plg-R in adipose function, metabolic homeostasis, and obesity.

Methods: We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)-induced obese mice together with immunofluorescence and real-time polymerase chain reaction to study adipose expression of Plg-R .

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The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to function as plasminogen receptors. Here, we review studies demonstrating that plasminogen bound to cells, in addition to plasminogen directly bound to fibrin, plays a major role in regulating fibrin surveillance. We focus on the ability of specific plasminogen receptors on eukaryotic cells to promote fibrinolysis in the in vivo setting by reviewing data obtained predominantly in murine models.

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Wound healing is a complex physiologic process that proceeds in overlapping, sequential steps. Plasminogen promotes fibrinolysis and potentiates the inflammatory response during wound healing. We have tested the hypothesis that the novel plasminogen receptor, Plg-R, regulates key steps in wound healing.

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Plasminogen activation rates are enhanced by cell surface binding. We previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules, but secretion of plasminogen from platelets has not been studied.

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Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal lysine functions to tether plasminogen to cell surfaces. Overexpression of Plg-R increases cell surface plasminogen binding capacity while genetic deletion of Plg-R decreases plasminogen binding.

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t-PA has a widespread neuroendocrine distribution including prominent expression in chromaffin cells of the sympathoadrenal system. Chromaffin cell t-PA is sorted into catecholamine storage vesicles and co-released with catecholamines in response to sympathoadrenal activation, suggesting that catecholamine storage vesicles may serve as a reservoir for the rapid release of t-PA. Chromogranin A (CgA), a major core protein in secretory vesicles throughout the neuroendocrine system, may play a crucial role in targeting proteins into the regulated secretory pathway, by forming aggregated "granin" complexes to which other proteins destined for the regulated secretory vesicle bind and become separated from constitutively secreted proteins in the trans-Golgi network (TGN).

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Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays an important role in inflammation resolution and induces remarkable macrophage phenotypic and functional changes. Here, we investigated the effects of deletion of either plasminogen (Plg) or the Plg receptor, Plg-R, on the resolution of inflammation.

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Membrane-bound plasmin is used by immune cells to degrade extracellular matrices, which facilitates migration. The plasminogen receptor Plg-R is expressed by immune cells, including monocytes and macrophages. Among monocytes and macrophages, distinct subsets can be distinguished based on cell surface markers and pathophysiological function.

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In this issue of , Mantuano et al in the Gonias laboratory elucidate a novel, protease-independent signaling pathway by which tissue plasminogen activator (tPA) negatively regulates the innate immune response of macrophages and neutralizes lipopolysaccharide (LPS) toxicity in vivo.

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Plasminogen activation is involved in many processes within the central nervous system, including synaptic plasticity, neuroinflammation and neurodegeneration. However, the mechanisms that regulate plasminogen activation in the brain still remain unknown. Here we demonstrate that astrocytes participate in this regulation by two mechanisms.

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Inflammation resolution is an active process that functions to restore tissue homeostasis. The participation of the plasminogen (Plg)/plasmin (Pla) system in the productive phase of inflammation is well known, but its involvement in the resolution phase remains unclear. Therefore, we aimed to investigate the potential role of Plg/Pla in key events during the resolution of acute inflammation and its underlying mechanisms.

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In this issue of Blood, Motley et al have identified a novel and unexpected mechanism for clearance of extravascular fibrin that is accomplished by a specific proinflammatory macrophage population and is dependent upon active plasmin, yet independent of known fibrinogen receptors.

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In this issue of Blood, Das et al assign a very novel and unanticipated function to plasminogen by showing that it is an enhancer of the phagocytic function of macrophages.

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Plasminogen (PLG) is the zymogen of plasmin, the major enzyme that degrades fibrin clots. In addition to its binding and activation on fibrin clots, PLG also specifically interacts with cell surfaces where it is more efficiently activated by PLG activators, compared with the reaction in solution. This results in association of the broad-spectrum proteolytic activity of plasmin with cell surfaces that functions to promote cell migration.

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The interaction of plasminogen with cell surfaces results in promotion of plasmin formation and retention on the cell surface. This results in arming cell surfaces with the broad-spectrum proteolytic activity of plasmin. Over the past quarter century, key functional consequences of the association of plasmin with the cell surface have been elucidated.

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When plasminogen binds to cells its activation to plasmin is markedly enhanced compared to the reaction in solution. Thus, cells become armed with the broad spectrum proteolytic activity of plasmin. Cell-surface plasmin plays a key role in macrophage recruitment during the inflammatory response.

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Binding of Glu-plasminogen (the native, circulating form of the zymogen) to cells results in enhancement of its activation. Cell-associated plasmin proteolytic activity is a key component of physiologic and pathologic processes requiring extracellular matrix degradation. Recently, we developed antiplasminogen mAbs that recognize receptor-induced binding sites (RIBS) in Glu-plasminogen and, therefore, preferentially react with cell-associated Glu-plasminogen in the presence of soluble Glu-plasminogen.

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Localization of plasmin on macrophages and activation of pro-MMP-9 play key roles in macrophage recruitment in the inflammatory response. These functions are promoted by plasminogen receptors exposing C-terminal basic residues on the macrophage surface. Recently, we identified a novel transmembrane plasminogen receptor, Plg-R(KT), which exposes a C-terminal lysine on the cell surface.

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