Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death

Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death

Abstract Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent...

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Bibliographic Details
Main Authors: Tom E. Mollnes, Neeltina M. Jager, Petra J. Ottens, Camilla Schjalm, Zwanida J. Veldhuis, Henri G. D. Leuvenink, Søren E. Pischke
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Scientific Reports
Subjects:
Brain death
Donor
Inflammation
Complement
CD14
Kidney
Online Access:https://doi.org/10.1038/s41598-025-12071-x
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Summary:Abstract Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent BD-mediated innate immune inflammation. BD was induced in mice either untreated, treated with a C5 inhibitor, a CD14 inhibitor, or both. Blood and kidneys were collected after three hours. Cytokines were analyzed using enzyme-immuno assays and qPCR. In plasma, a substantial increase in interleukin-6 (IL-6), KC (IL-8 analogue), IL-12, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein MIP-1α, MIP-1β, eotaxin, RANTES and G-CSF (median 90-fold increase) were observed in BD animals compared to sham (all p < 0.01). In kidneys, BD substantially induced IL-6, KC, TNF, MCP-1, P-Selectin, and VCAM-1 (all p < 0.01). In plasma, C5 and CD14 inhibition, either single or in combination, virtually abolished all cytokines in the BD animals (> 90% for six cytokines and 70–90% for three) (all p < 0.01). In kidneys, the effect of inhibition was similar (> 90% for IL-6 and KC and 60–80% for TNF and MCP-1 (all p < 0.01). Single and combined inhibition of C5 and CD14 efficiently prevented BD-induced systemic inflammation and reduced local kidney inflammation in a mouse model.
ISSN:2045-2322

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