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Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):271-276. doi: 10.1073/pnas.1810020116. Epub 2018 Dec 17.

Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release.

Author information

Clinic of Neurology, Institute of Translational Neurology, University of Münster, 48149 Münster, Germany;
Clinic of Neurology, Institute of Translational Neurology, University of Münster, 48149 Münster, Germany.
Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.
Clinic of Anesthesiology, Intensive Care and Pain Medicine, Experimental and Clinical Haemostasis, University of Münster, 48149 Münster, Germany.
Department of Neurology, University Hospital Essen, 45147 Essen, Germany.


Blood-brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2-dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.


EAE; coagulation; multiple sclerosis; neuroinflammation; plasma kallikrein

[Available on 2019-07-02]

Conflict of interest statement

The authors declare no conflict of interest.

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