Surreal illustration of a blood-brain barrier being repaired, symbolizing neuroinflammation treatment.

Unlocking the Brain's Defenses: How Plasma Kallikrein Impacts Neuroinflammation

Samir D’Costa in Health & Wellness June 2025 • 4 min read.

"New research illuminates how plasma kallikrein (KK) influences immune cell trafficking during neuroinflammation, offering potential therapeutic targets for multiple sclerosis and other CNS disorders."

The central nervous system (CNS) is usually a fortress, heavily guarded to prevent unwanted intruders. One of its primary defense mechanisms is the blood-brain barrier (BBB), a highly selective membrane that prevents harmful substances and immune cells from entering the brain. However, in neuroinflammatory disorders like multiple sclerosis (MS), this barrier becomes compromised, allowing immune cells to infiltrate the CNS and cause damage.

Recent studies suggest that the kallikrein-kinin system (KKS), traditionally known for its role in blood coagulation and inflammation, might also play a significant role in the breakdown of the BBB. This system involves a complex interplay of enzymes and proteins, including plasma kallikrein (KK), which is the focus of this research. Plasma kallikrein (KK) is derived from its precursor, plasma prekallikrein (PK).

A groundbreaking study led by Kerstin Göbel and colleagues sheds light on how plasma kallikrein modulates immune cell trafficking during neuroinflammation. By understanding these mechanisms, researchers hope to find new therapeutic targets to protect the brain and combat diseases like MS.

The Role of Plasma Kallikrein in BBB Disruption

Surreal illustration of a blood-brain barrier being repaired, symbolizing neuroinflammation treatment.

The study begins by identifying plasma kallikrein (KK) as a direct modulator of BBB integrity. They observed markedly elevated levels of plasma prekallikrein (PK), the precursor of KK, in active CNS lesions of MS patients. This initial observation was a critical clue, suggesting that the KKS might be more involved in MS pathology than previously thought.

To investigate further, the team used experimental autoimmune encephalomyelitis (EAE) models, which mimic MS in mice. By genetically deleting PK (Klkb1-/- mice) or pharmacologically blocking it, they found that mice became less susceptible to EAE. This protection was accompanied by a remarkable reduction in BBB disruption and CNS inflammation, underlining the importance of PK and its enzymatic product KK.

PK levels are significantly elevated in the CNS lesions of MS patients.
Mice deficient in PK are less susceptible to EAE.
Reduced BBB disruption and CNS inflammation observed in PK-deficient mice.
KK influences endothelial cell function via PAR2.

In vitro analyses revealed that KK modulates endothelial cell function in a protease-activated receptor-2 (PAR2)-dependent manner. This activation leads to an up-regulation of cellular adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1) and Vascular Cell Adhesion Molecule 1 (VCAM-1), which amplify leukocyte trafficking. By demonstrating that PK directly regulates BBB integrity, the study underscores the potential of KK inhibition as a strategy to decrease BBB damage and cell invasion during neuroinflammation.

Future Implications and Therapeutic Potential

These findings open new avenues for therapeutic interventions in MS and other neuroinflammatory disorders. By targeting KK and its related pathways, researchers may be able to develop treatments that protect the BBB, reduce immune cell infiltration, and ultimately slow down or prevent the progression of these debilitating diseases. Further studies are needed, but the future looks promising for innovative therapies aimed at modulating the kallikrein-kinin system to preserve brain health.

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This article is based on research published under:

DOI-LINK: 10.1073/pnas.1810020116, Alternate LINK

Title: Plasma Kallikrein Modulates Immune Cell Trafficking During Neuroinflammation Via Par2 And Bradykinin Release

Subject: Multidisciplinary

Journal: Proceedings of the National Academy of Sciences

Publisher: Proceedings of the National Academy of Sciences

Authors: Kerstin Göbel, Chloi-Magdalini Asaridou, Monika Merker, Susann Eichler, Alexander M. Herrmann, Eva Geuß, Tobias Ruck, Lisa Schüngel, Linda Groeneweg, Venu Narayanan, Tilman Schneider-Hohendorf, Catharina C. Gross, Heinz Wiendl, Beate E. Kehrel, Christoph Kleinschnitz, Sven G. Meuth

Published: 2018-12-17

Everything You Need To Know

What is plasma kallikrein (KK), and how is it relevant to neuroinflammation?

Plasma kallikrein (KK) is an enzyme derived from its precursor, plasma prekallikrein (PK), and is part of the kallikrein-kinin system (KKS). This system is traditionally known for its role in blood coagulation and inflammation. In the context of neuroinflammation, plasma kallikrein (KK) has been identified as a modulator of blood-brain barrier (BBB) integrity, influencing immune cell trafficking into the central nervous system (CNS). Elevated levels of plasma prekallikrein (PK) have been observed in active CNS lesions of multiple sclerosis (MS) patients, suggesting its involvement in the disease's pathology. The absence of Plasma prekallikrein (PK) reduces the breakdown of the BBB.

What is the role of the blood-brain barrier (BBB) in the central nervous system (CNS), and why is its disruption significant in conditions like multiple sclerosis (MS)?

The blood-brain barrier (BBB) is a highly selective membrane that protects the central nervous system (CNS) by preventing harmful substances and immune cells from entering the brain. In neuroinflammatory disorders like multiple sclerosis (MS), the integrity of the blood-brain barrier (BBB) is compromised, allowing immune cells to infiltrate the CNS and cause damage. Plasma kallikrein (KK) has been identified as a modulator of blood-brain barrier (BBB) integrity, influencing immune cell trafficking into the central nervous system (CNS).

How did researchers use experimental autoimmune encephalomyelitis (EAE) models to study the impact of plasma prekallikrein (PK) on neuroinflammation?

Researchers used experimental autoimmune encephalomyelitis (EAE) models, which mimic multiple sclerosis (MS) in mice, to investigate the role of plasma prekallikrein (PK). By genetically deleting PK (Klkb1-/- mice) or pharmacologically blocking it, they observed that mice became less susceptible to EAE. This protection was accompanied by a reduction in blood-brain barrier (BBB) disruption and central nervous system (CNS) inflammation, highlighting the importance of plasma prekallikrein (PK) and its enzymatic product, plasma kallikrein (KK).

How does plasma kallikrein (KK) influence endothelial cell function, and what is the role of protease-activated receptor-2 (PAR2) in this process?

Plasma kallikrein (KK) modulates endothelial cell function via protease-activated receptor-2 (PAR2). This activation leads to an up-regulation of cellular adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1) and Vascular Cell Adhesion Molecule 1 (VCAM-1). These adhesion molecules amplify leukocyte trafficking, contributing to neuroinflammation. This process demonstrates how plasma kallikrein (KK) influences the movement of immune cells across the blood-brain barrier (BBB).

What are the potential therapeutic implications of targeting plasma kallikrein (KK) and its related pathways for treating neuroinflammatory disorders like multiple sclerosis (MS)?

Targeting plasma kallikrein (KK) and its related pathways within the kallikrein-kinin system (KKS) could lead to new treatments that protect the blood-brain barrier (BBB), reduce immune cell infiltration, and potentially slow down or prevent the progression of neuroinflammatory diseases like multiple sclerosis (MS). Developing therapies aimed at modulating the kallikrein-kinin system to preserve brain health is a promising avenue for future research. However, further studies are needed to fully understand the complex interactions within this system and to develop safe and effective treatments.