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

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

doi:10.1073/pnas.1810020116

Cited by 42 publications

(36 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Future studies will be required to determine a crystal structure of the PK zymogen to establish whether this mirrors the conformation observed for the FXI zymogen and to determine whether the PKa apple 3 domain is utilized for substrate recruitment as it is in FXIa. Other substrates reported for PKa include the integral membrane proteins protease activated receptor (PAR), PAR‐1, and PAR‐2 implicated in regulation of blood‐brain barrier integrity and platelet activation . It is interesting to note that the P1‐P1′ cleavage site Arg‐Ser in the PAR‐1 and PAR‐2 sequences also occurs in the classical PKa substrate HK to release bradykinin .…”

Section: Discussionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Zymogen PK is activated to PKa and cleaves substrates kininogen and FXII contributing to bradykinin generation. Monomeric PKa and dimeric homologue FXI utilize the N‐terminal apple domains to recruit substrates. A high‐resolution 1.3 Å structure of full‐length PKa reveals an active conformation of the protease and apple domains. The PKa protease and four‐apple domain disc organization is 180° rotated compared to FXI. Summary BackgroundPlasma prekallikrein (PK) and factor XI (FXI) are apple domain‐containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin release, inflammation, and thrombosis pathways. ObjectiveTo investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI. MethodsA series of recombinant full‐length PKa and FXI constructs and variants were developed and the crystal structures determined. Results and conclusionsA 1.3 Å structure of full‐length PKa reveals the protease domain positioned above a disc‐shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulfide and structural differences in the apple 4 domain that prevents dimer formation in PK as opposed to FXI. Two latchlike loops (LL1 and LL2) extend from the PKa protease domain to form interactions with the apple 1 and apple 3 domains, respectively. A major unexpected difference in the PKa structure compared to FXI is the 180° disc rotation of the apple domains relative to the protease domain. This results in a switched configuration of the latch loops such that LL2 interacts and buries portions of the apple 3 domain in the FXI zymogen whereas in PKa LL2 interacts with the apple 1 domain. Hydrogen‐deuterium exchange mass spectrometry on plasma purified human PK and PKa determined that regions of the apple 3 domain have increased surface exposure in PKa compared to the zymogen PK, suggesting conformational change upon activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…The increased peroxiredoxin 6 (PRDX6) expression in astrocytes also alleviated clinical score in EAE mice [7]. Plasma kallikrein inhibition decreased BBB damage and cell invasion during neuroinflammation [8]. S1PR2 knockout decreased BBB leakage, the extent of demyelinated area, and the clinical disability [9].…”

Section: Introductionmentioning

confidence: 98%

Mesenchymal Stem Cells Attenuated Blood-Brain Barrier Disruption via Downregulation of Aquaporin-4 Expression in EAE Mice

Liu

et al. 2020

Mol Neurobiol

View full text Add to dashboard Cite

Blood-brain barrier disruption is one of the hallmarks of multiple sclerosis. Mesenchymal stem cells showed great potential for the multiple sclerosis therapy. However, the effect of mesenchymal stem cells on blood-brain barrier in multiple sclerosis remains unclear. Here, we investigated whether mesenchymal stem cells transplantation protected blood-brain barrier integrity and further explored possible underlying mechanisms. Adult female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein peptide33-55 (MOG33-55) to induce experimental autoimmune encephalomyelitis (EAE). Mesenchymal stem cells (5 × 10 5) were transplanted via tail vein at disease onset. In the cell culture, we examined lipopolysaccharide-induced AQP4 upregulation in astrocytes. Results indicated that mesenchymal stem cells therapy improved neurobehavioral outcomes in EAE mice, reduced inflammatory cell infiltration, IgG protein leakage, and demyelination in spinal cord. Mesenchymal stem cells therapy also increased tight junction protein expression. In addition, mesenchymal stem cells downregulated AQP4 and A 2B adenosine receptor (A 2B AR) expression in EAE mice in spinal cord. We found that MSCs-conditioned medium (MCM) reduced the expression of inflammatory cytokines, AQP4 and A 2B AR in lipopolysaccharide-activated astrocytes. BAY-60-6583 (a selective A 2B AR agonist) reversed the MCM-induced AQP4 downregulation and increased p38 MAPK phosphorylation. Furthermore, the upregulation effects of A 2B AR agonist were eliminated when treated with p38 MAPK inhibitor SB203580. Thus, we concluded that mesenchymal stem cells alleviated blood-brain barrier disruption by downregulating AQP4 in multiple sclerosis, possibly through inhibiting the A 2B AR/p38 MAPK signaling pathway. Our work suggests that mesenchymal stem cells exert beneficial effect through maintaining blood-brain barrier integrity in EAE mice.

show abstract

“…The kallikrein-kinin system (KKS) consists of kinins, kallikreins, kininogens, and kinin receptors. Kinin plays its role by binding to the receptor, resulting in neuroprotective effect [8]. However, kinin could not be used as a drug because of its short half-life [9].…”

Section: Introductionmentioning

confidence: 99%

Human Urinary Kallidinogenase Reduces Lipopolysaccharide-Induced Neuroinflammation and Oxidative Stress in BV-2 Cells

Zhao

Liu

et al. 2019

Pain Research and Management

View full text Add to dashboard Cite

Migraine is one of the most common neurological disorders which poses significant socioeconomic burden worldwide. Neuroinflammation and oxidative stress both play important roles in the pathogenesis of migraine. Human urinary kallidinogenase (UK) is a tissue kallikrein derived from human urine. Increasing evidence suggests that UK may protect against ischemic stroke, but UK’s treatment potential against migraine remains to be explored. Immortal BV-2 murine microglial cells were treated with UK (125 nM, 250 nM, and 500 nM) and then given lipopolysaccharides (LPS, 1000 ng/mL). Cell viability of BV-2 cells was tested by the CCK-8 assay. Expressions of tumor necrosis factor-α (TNFα), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were examined with the ELISA method and western blot. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to determine oxidative stress. Our results showed that LPS administration increased the levels of proinflammatory cytokines (TNFα, PGE2, IL-6, and IL-1β) and oxidative stress (ROS and MDA) when compared with the control group and decreased significantly upon introduction with UK. Taken together, UK treatment reduced LPS-induced neuroinflammation and oxidative stress in a dose-dependent manner, which might be a potential treatment of migraine.

show abstract

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

Cited by 42 publications

References 44 publications

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Mesenchymal Stem Cells Attenuated Blood-Brain Barrier Disruption via Downregulation of Aquaporin-4 Expression in EAE Mice

Human Urinary Kallidinogenase Reduces Lipopolysaccharide-Induced Neuroinflammation and Oxidative Stress in BV-2 Cells

Contact Info

Product

Resources

About