Dual inhibition of complement C5 and CD14 attenuates inflammation in a cord blood model

Bjerkhaug, Aline Uhirwa; Granslo, Hildegunn Norbakken; Cavanagh, Jorunn Pauline; Høiland, Ina Isabella; Ludviksen, Judith Krey; Lau, Corinna; Espevik, Terje; Mollnes, Tom Eirik; Klingenberg, Claus

doi:10.1038/s41390-023-02489-2

Cited by 1 publication

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“…The lepirudin whole-blood model is based on a highly specific inhibition of thrombin to avoid coagulation, where all other molecular and cell systems are kept open and can mutually interact [ 16 ]. The model has previously been successfully used to study the response of the complement and toll-like receptor (TLR) systems to gram-negative and gram-positive bacteria [ 17 ]. We, therefore, hypothesized that this model would also elucidate the contributions of the complement system and other facets of the initial innate immune response to A. fumigatus conidia.…”

Section: Introductionmentioning

confidence: 99%

The inflammatory response induced by Aspergillus fumigatus conidia is dependent on complement activation - Insight from a whole blood model

Fageräng,

Götz,

Cyranka

et al. 2024

J Innate Immun

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Introduction: We aimed to elucidate the inflammatory response of Aspergillus fumigatus conidia in a whole-blood model of innate immune activation and to compare it with the well-characterized inflammatory reaction to E. coli. Methods: Employing a human lepirudin whole-blood model, we analyzed complement and leukocyte activation by measuring the sC5b-9 complex and assessing CD11b expression. A 27-multiplex system was used for quantification of cytokines. Selective cell removal from whole blood and inhibition of C3, C5, and CD14 were also applied. Results: Our findings demonstrated a marked elevation in sC5b-9 and CD11b post-A. fumigatus incubation. Thirteen cytokines (TNF, IL-1β, IL-1ra, IL-4, IL-6, IL-8, IL-17, IFNγ, MCP-1, MIP-1α, MIP-1β, FGF-basic, and G-CSF) showed increased levels. A generally lower level of cytokine release and CD11b expression was observed with A. fumigatus conidia than with E. coli. Notably, monocytes were instrumental in releasing all cytokines except MCP-1. IL-1ra was found to be both monocyte and granulocyte-dependent. Pre-inhibiting with C3 and CD14 inhibitors resulted in decreased release patterns for six cytokines (TNF, IL-1β, IL-6, IL-8, MIP-1α and MIP-1β), with minimal effects by C5-inhibition. Conclusion: A. fumigatus conidia induced complement activation comparable to E. coli, whereas CD11b expression and cytokine release were lower, underscoring distinct inflammatory responses between these pathogens. Complement C3 inhibition attenuated cytokine release indicating a C3-level role of complement in A. fumigatus immunity.

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Section: Introductionmentioning

confidence: 99%