t-PA acts as a cytokine to regulate lymphocyte–endothelium adhesion in experimental autoimmune encephalomyelitis

Wang, Jinghua; Zhang, Xin; Mu, Lili; Zhang, Mingqing; Gao, Zhongming; Zhang, Jia; Yao, Xiuhua; Liu, Chuanliang; Wang, Guangyou; Wang, Dandan; Kong, Qingfei; Liu, Yumei; Li, Na; Sun, Bo; Li, Hulun

doi:10.1016/j.clim.2014.03.004

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…Increased astrocytic CXCL12 expression in MS tissue specimens is associated with CNS inflammation [ 78 ]. Furthermore, IL-6 and tissue plasminogen activators (tPA), produced by reactive astrocytes, upregulate adhesion molecules on the endothelial cells, such as E-selectin, VCAM, ICAM, and CD44 ligand hyaluronan, resulting in increased endothelial–T-cell binding [ 79 , 80 ]. Decreased expression of connexin 43 (Cx43) in activated astrocytes is also linked to elevated adhesion molecule expression in the endothelial cell [ 81 ], and to rapidly progressive MS [ 82 ].…”

Section: Astrocytes As Mediators Of Ms and Eae Pathologymentioning

confidence: 99%

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

Aharoni

Arnon

2021

IJMS

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In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties.

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Section: Astrocytes As Mediators Of Ms and Eae Pathologymentioning

confidence: 99%

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

Aharoni

Arnon

2021

IJMS

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“…Initially, Lu et al described that tPA - / - developed a more severe form of EAE but with a delayed onset in the disease [57] . Although most studies corroborated this finding and showed a protective role of tPA [8] , [56] , [59] , others reported a detrimental function of tPA in the pathogenesis of EAE with either tPA deficiency which results in a less severe form of EAE or tPA administration that increases the severity of EAE [9] , [51] . These inconsistencies between several studies may be attributed to the differences in the experimental protocols including myelin antigen doses, sex and age of the animals or the number of immunizations/boosts.…”

Section: The Role Of Tpa In T Cell Activitymentioning

confidence: 90%

“…The tPA inhibitor PAI-1 is necessary to macrophage migration by promoting MAC1 internalization and cell detachment [50] . tPA regulates the adhesion of T cells to brain endothelial cells and increases T cell migration in vitro [51] . To this end, tPA binds to the cell membrane receptor LRP1 on endothelial cells via a “cytokine-like” action to drive the up-regulation of the adhesion molecule intercellular adhesion molecules-1 (ICAM-1) ( Fig 1 C ).…”

Section: Role Of the Plasminogen Activation System In Migration And Adhesion Of Immune Cellsmentioning

confidence: 99%

“…To this end, tPA binds to the cell membrane receptor LRP1 on endothelial cells via a “cytokine-like” action to drive the up-regulation of the adhesion molecule intercellular adhesion molecules-1 (ICAM-1) ( Fig 1 C ). Of note, tPA effect is also observed in vivo since the intravenous administration of tPA enhances ICAM-1 expression on brain endothelial cells and is associated with a worsening of EAE, induced by immunization with a myelin antigen such as myelin oligodendrocyte glycoprotein (MOG) [51] . These data indicate a contribution of tPA in T-cell mediated-immunopathology and neuroinflammation.…”

Section: Role Of the Plasminogen Activation System In Migration And Adhesion Of Immune Cellsmentioning

confidence: 99%

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Roles of the tissue-type plasminogen activator in immune response

Seillier

Hélie

Petit

et al. 2022

Cellular Immunology

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“…t-PA promotes microglia activation in the brain via LRP-1 and annexin II [ 14 , 15 , 16 ], activated glial cells release most of this fibrinolytic enzyme with autocrine effects fueling a vicious loop with pro-inflammatory and neurotoxic effects [ 16 , 17 ]. Furthermore, tPA contributes to the adhesion and transmigration of monocytes and T-cells in vitro through NMDAR and LRP-1 mediated signaling [ 18 , 19 ]. Yet, whether tPA also leads to the pro-inflammatory activation of macrophages remains to be fully elucidated with different reports showing heterogeneous results [ 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1)

Liberale

Bertolotto

Minetti

et al. 2020

IJMS

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Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden chamber migration assay and checkerboard analysis we showed a dose-dependent chemotactic effect of r-TPA with a maximum effect reached by 0.03 mg/mL (0.003–1 mg/mL). Pre-incubation with MAP kinases inhibitors allowed the identification of PI3K/Akt, but not ERK1/2 as the intracellular pathway mediating the observed effects. Furthermore, by means of real-time PCR, immunocytochemistry and cytofluorimetry we demonstrated that the r-tPA receptor low density lipoprotein receptor-related protein 1 (LRP-1) is synthetized and expressed by neutrophils in response to r-tPA and TNF-α. Inhibition of LRP-1 by receptor-associated protein (RAP), prevented r-tPA-mediated F-actin polymerization, migration and signal through Akt but not ERK1/2. Lastly, also neutrophil degranulation in response to r-tPA seems to be mediated by LRP-1 under adhesion conditions. In conclusion, we show that r-tPA induces neutrophil chemotaxis through LRP-1/Akt pathway. Blunting r-tPA-mediated neutrophil activation might be beneficial as an adjuvant therapy to thrombolysis in this setting.

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t-PA acts as a cytokine to regulate lymphocyte–endothelium adhesion in experimental autoimmune encephalomyelitis

Cited by 11 publications

References 41 publications

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

Roles of the tissue-type plasminogen activator in immune response

Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1)

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