The Low-Density Lipoprotein Receptor-Related Protein 1 Mediates Tissue-Type Plasminogen Activator-Induced Microglial Activation in the Ischemic Brain

Abstract

Microglia are the immune cells of the central nervous system (CNS) that become activated in response to pathological situations such as cerebral ischemia. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in the intravascular space and the CNS. The low-density lipoprotein receptor-related protein 1 (LRP1) is a member of the low-density lipoprotein receptor gene family found in neurons, astrocytes, and microglia. The present study investigated whether the interaction between tPA and microglial LRP1 plays a role in cerebral ischemia-induced microglial activation. We found that middle cerebral artery occlusion (MCAO) induces microglial activation in both wild-type and plasminogen-deficient (Plg ؊/؊ ) mice. In contrast, MCAO-induced microglial activation is significantly decreased in tPA-deficient (tPA ؊/؊ ) mice and in mice that lack LRP1 in microglial cells (macLRP ؊ ). We observed a significant increase in microglial activation when tPA ؊/؊ mice received treatment with murine tPA after MCAO. In contrast, treatment of macLRP ؊ mice with tPA did not have an effect on the extent of microglial activation. Finally, both the volume of the ischemic lesion as well as inducible nitric oxide synthase production were significantly decreased in macLRP ؊ mice and macLRP

Tissue-type Plasminogen Activator (tPA) Promotes M1 Macrophage Survival through p90 Ribosomal S6 Kinase (RSK) and p38 Mitogen-activated Protein Kinase (MAPK) Pathway

“…tPA has been shown to modulate macrophage accumulation in various organs (14 -19). In an acute brain injury model, tPA was shown to mediate F4/80 macrophage accumulation and activation in the ischemic brain (16). It was also found that tPA promotes the accumulation of macrophages or other leukocytes in both models of acute (18) and chronic kidney injury (14,19).…”

Annexin A2 Combined with Low-Dose tPA Improves Thrombolytic Therapy in a Rat Model of Focal Embolic Stroke

“…Furthermore, a number of reports have suggested new strategies for reducing the tPA dose, but enhancing plasmin generation or activity to improve safety of tPA thrombolytic therapy. These include the findings that (1) local infusion of plasmin into the thrombus does not cause excessive bleeding within six-fold greater than the effective thrombolytic dose of tPA used (Marder et al, 2001); (2) antiplasmin quickly (in 1 sec) neutralizes plasmin that appears in the circulation (Marder et al, 2001), whereas tPA has longer half life (4 to 5 mins), and can cross the blood-brain barrier, whether damaged or intact, through low-density lipoprotein receptor-related protein-dependent and independent mechanisms, further weaking blood-brain barrier integrity and worsening brain damage (Benchenane et al, 2005;Yepes et al, 2003); (3) tPA can induce plasmin-independent MMP-9 up-regulation and microglia activation in stroke animal models (Aoki et al, 2002;Zhang et al, 2009). In addition, initial experimental evidence suggested that rA2 administration alone in vivo has not exhibited any organ specific or systematic complications (Ishii et al, 2001;Tanaka et al, 2007).…”

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

“…Additional substrates, binding proteins, or receptors for tPA include the NMDAR, the low-density lipoprotein receptorrelated protein (LRP), and annexin-II (Siao and Tsirka, 2002;Samson et al, 2008;Zhang et al, 2009). For instance, tPA regulates NMDAR signaling, leading to neuronal cell death in pathological conditions, such as stroke (Nicole et al, 2001).…”