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Bradykinin B1 receptor signaling triggers complement activation on endothelial cells

Lopatko Fagerström, Ingrid LU ; Gerogianni, Alexandra LU ; Wendler, Markus LU orcid ; Arvidsson, Ida LU ; Tontanahal, Ashmita LU ; Kristoffersson, Ann-Charlotte LU ; Qadri, Fatimunnisa ; Bader, Michael and Karpman, Diana LU orcid (2025) In Frontiers in Immunology 16. p.01-12
Abstract
Introduction: The complement and kallikrein-kinin systems (KKS) are both activated during vascular inflammation, and there are many known interactions between the two systems. This study investigated if KKS activation induced complement activation on endothelial cells, and if activation was dependent on bradykinin B1 receptor (B1R) signaling.

Methods: KKS was activated in normal human serum by kaolin or activated factor XII (FXIIa). ADP-preactivated primary glomerular endothelial cells (PGECs) were incubated with serum, with or without kaolin or FXIIa, and with or without the B1R antagonist (R715) or the inositol triphosphate receptor (IP3R) inhibitor 2-aminoethoxydiphenyl borate (2-APB). Complement factors C3a, factor Ba and... (More)
Introduction: The complement and kallikrein-kinin systems (KKS) are both activated during vascular inflammation, and there are many known interactions between the two systems. This study investigated if KKS activation induced complement activation on endothelial cells, and if activation was dependent on bradykinin B1 receptor (B1R) signaling.

Methods: KKS was activated in normal human serum by kaolin or activated factor XII (FXIIa). ADP-preactivated primary glomerular endothelial cells (PGECs) were incubated with serum, with or without kaolin or FXIIa, and with or without the B1R antagonist (R715) or the inositol triphosphate receptor (IP3R) inhibitor 2-aminoethoxydiphenyl borate (2-APB). Complement factors C3a, factor Ba and C5b-9 were evaluated by ELISA or immunoblotting. B1/B2 receptor double knock-out and wild-type mice were injected with lipopolysaccharide from E. coli B5:O55, to induce KKS activation.

Results: Supernatants from PGECs incubated with serum exposed to kaolin or FXIIa exhibited higher levels of Ba and C5b-9, which were significantly reduced in the presence of the B1R antagonist. Complement activation induced by FXIIa was also reduced in the presence of the IP3R inhibitor. Likewise, cell lysates showed higher levels of C3a and C5b-9 in the presence of kaolin and FXIIa, and complement activation was significantly reduced in the presence of the B1R antagonist. B1/B2 receptor double knock-out mice exhibited less C3 and C5b-9 deposition in glomeruli compared to wild-type mice.

Conclusion: This study demonstrates that KKS activation contributes to complement activation on the endothelium by B1R signaling. Blocking the B1R may have a role in reducing complement deposition and its effects on the endothelium. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Immunology
volume
16
article number
1527065
pages
01 - 12
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85218688971
  • pmid:39991158
ISSN
1664-3224
DOI
10.3389/fimmu.2025.1527065
language
English
LU publication?
yes
id
23d7cb1d-6ed0-4c5b-863b-5a3cca33fd76
date added to LUP
2025-01-29 09:17:47
date last changed
2025-05-01 03:00:02
@article{23d7cb1d-6ed0-4c5b-863b-5a3cca33fd76,
  abstract     = {{Introduction: The complement and kallikrein-kinin systems (KKS) are both activated during vascular inflammation, and there are many known interactions between the two systems. This study investigated if KKS activation induced complement activation on endothelial cells, and if activation was dependent on bradykinin B1 receptor (B1R) signaling.<br/><br/>Methods: KKS was activated in normal human serum by kaolin or activated factor XII (FXIIa). ADP-preactivated primary glomerular endothelial cells (PGECs) were incubated with serum, with or without kaolin or FXIIa, and with or without the B1R antagonist (R715) or the inositol triphosphate receptor (IP3R) inhibitor 2-aminoethoxydiphenyl borate (2-APB). Complement factors C3a, factor Ba and C5b-9 were evaluated by ELISA or immunoblotting. B1/B2 receptor double knock-out and wild-type mice were injected with lipopolysaccharide from E. coli B5:O55, to induce KKS activation.<br/><br/>Results: Supernatants from PGECs incubated with serum exposed to kaolin or FXIIa exhibited higher levels of Ba and C5b-9, which were significantly reduced in the presence of the B1R antagonist. Complement activation induced by FXIIa was also reduced in the presence of the IP3R inhibitor. Likewise, cell lysates showed higher levels of C3a and C5b-9 in the presence of kaolin and FXIIa, and complement activation was significantly reduced in the presence of the B1R antagonist. B1/B2 receptor double knock-out mice exhibited less C3 and C5b-9 deposition in glomeruli compared to wild-type mice.<br/><br/>Conclusion: This study demonstrates that KKS activation contributes to complement activation on the endothelium by B1R signaling. Blocking the B1R may have a role in reducing complement deposition and its effects on the endothelium.}},
  author       = {{Lopatko Fagerström, Ingrid and Gerogianni, Alexandra and Wendler, Markus and Arvidsson, Ida and Tontanahal, Ashmita and Kristoffersson, Ann-Charlotte and Qadri, Fatimunnisa and Bader, Michael and Karpman, Diana}},
  issn         = {{1664-3224}},
  language     = {{eng}},
  month        = {{02}},
  pages        = {{01--12}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Bradykinin B1 receptor signaling triggers complement activation on endothelial cells}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2025.1527065}},
  doi          = {{10.3389/fimmu.2025.1527065}},
  volume       = {{16}},
  year         = {{2025}},
}