Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking

Göbel, Kerstin; Pankratz, Susann; Schneider‐Hohendorf, Tilman; Bittner, Stefan; Schuhmann, Michael K.; Langer, Harald F.; Stoll, Guido; Wiendl, Heinz; Kleinschnitz, Christoph; Meuth, Sven G.

doi:10.1016/j.jaut.2010.11.004

Cited by 76 publications

(66 citation statements)

References 51 publications

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“…Blocking of B1R dramatically reduced inflammatory processes and edema formation in models of acute ischemic stroke, 13 traumatic brain injury, 12 and multiple sclerosis. 11 The corresponding findings in different mouse models bearing genetic defects in the contact-kinin system suggest that thrombosis and inflammation are closely intertwined during focal cerebral ischemia. This goes congruent with the novel concept of ischemic stroke being a thrombo-inflammatory disease rather than a pure vessel-occlusive disease.…”

Section: Discussionmentioning

confidence: 99%

“…10 Activation of the contact-kinin system by FXII triggers cleavage of KNG by plasma kallikrein and subsequent release of the proinflammatory peptide hormone bradykinin. The contact-kinin system occupies a central position in the pathophysiology of different neurologic disease models that mimic, for example, multiple sclerosis 11 or traumatic brain injury. 12 In acute ischemic stroke activation of the contactkinin system fosters vascular permeability and stroke-related inflammation by the formation of short-lived kinins, while at the same time it is linked to thrombus formation via the FXII-driven intrinsic coagulation cascade.…”

Section: Introductionmentioning

confidence: 99%

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Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Langhauser¹,

Göb²,

Kraft³

et al. 2012

Blood

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123

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Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. Highmolecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng Ϫ/Ϫ mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng Ϫ/Ϫ mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. (Blood. 2012;120(19): 4082-4092) IntroductionThe pathology of ischemic stroke is complex and involves a myriad of distinct molecular pathways and cellular interactions. Among these, progressive thrombus formation in the cerebral microvasculature is a key process that can cause secondary infarct growth despite successful recanalization of larger proximal brain vessels both under experimental conditions as well as in humans. 1,2 We recently identified the intrinsic coagulation cascade as a novel and safe antithrombotic target for the prevention and treatment of acute ischemic stroke. 3 Genetic depletion or pharmacologic blockade of coagulation factor XII (FXII), the origin of the intrinsic pathway, markedly reduced intracerebral thrombus formation and infarct growth in mice without increasing the risk of bleeding complications. 4,5 Clot formation was also significantly reduced in several in vitro models of thrombosis after FXII inhibition. 5 Current pathophysiologic concepts also emphasize the importance of inflammatory mechanisms in stroke. 6 The cerebral endothelium is activated early during the course of an ischemic event, leading to the up-regulation of cell adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the blood stream into the brain parenchyma. Those cells attracted from the periphery in concert with resident cell populations (endothelial cells, microglia) secrete an array of soluble immune mediators such as cytokines and chemokines that perpetuate the inflammatory response to cause direct or indirect ti...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Langhauser¹,

Göb²,

Kraft³

et al. 2012

Blood

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121

123

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“…Conversely, in the vasogenic edema, the cellular signaling triggered by SE can induce proinflammatory cytokines release and increases the production of kinins [71][72][73][74][75][76][77][78]. The kinins along with the cytokines may affect the junction of blood vessel epithelial cells and reduce the integrity of the tight junctions in endothelial cells walls, leading to a dysfunction of the blood brain barrier and consequently increasing the vascular permeability and accumulation of extracellular fluid [63,70,79,80]. There are a number of studies showing robust evidence that IL-1β released following seizures may be pro-convulsant in experimental models of epilepsy [6,14,15,76,81].…”

Section: Discussionmentioning

confidence: 99%

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Amorim

Araújo

Valero

et al. 2017

Purinergic Signalling

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Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: SalineVehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the PilosiRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.

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“…Transmigration of CD4 + cells through an in vitro BBB model was assessed as described before (52,53). In brief, MBMEC were prepared from brains of C57BL/6 mice and cultured 5 d before use on 3.0-μm ColagenIV/fibronectin-coated Transwell Pore Polyester Membrane inserts (Corning).…”

Section: Methodsmentioning

confidence: 99%

Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis

Lanz

Becker

Osswald³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.

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Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking

Cited by 76 publications

References 51 publications

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis

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