C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages

The complement system mediates diverse regulatory immunological functions. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanis...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2023-11, Vol.12 (23), p.2707
Main Authors: Wright, Oliver, Harris, Anna, Nguyen, Van Dien, Zhou, You, Durand, Maxim, Jayyaratnam, Abbie, Gormley, Darren, O'Neill, Luke A J, Triantafilou, Kathy, Nichols, Eva Maria, Booty, Lee M
Format: Article
Language:English
Subjects:
Analysis
anaphylatoxin receptor
Anaphylatoxins
C5a
C5aR2
Cell lines
Cells
Cloning
complement
Complement component C5a
Complement system
CRISPR
Cytokines
Dosage and administration
Inflammation
innate immune sensing
Interferon
Interferon beta
Interferon regulatory factor 3
Kinases
Macrophages
Molecular modelling
Monocytes
pattern recognition receptor
Pattern recognition receptors
Proteins
Protocol
RNA sequencing
Signal transduction
Transcriptomics
β-Interferon
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Summary:The complement system mediates diverse regulatory immunological functions. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanisms are less clear. In this study, CRISPR-Cas9 was used to generate macrophage models lacking C5aR2, which were used to probe the role of C5aR2 in the context of PRR stimulation. cGAS and STING-induced IFN-β secretion was significantly increased in C5aR2 KO THP-1 cells and C5aR2-edited primary human monocyte-derived macrophages, and STING and IRF3 expression were increased, albeit not significantly, in C5aR2 KO cell lines implicating C5aR2 as a regulator of the IFN-β response to cGAS-STING pathway activation. Transcriptomic analysis by RNAseq revealed that nucleic acid sensing and antiviral signalling pathways were significantly up-regulated in C5aR2 KO THP-1 cells. Altogether, these data suggest a link between C5aR2 and nucleic acid sensing in human macrophages. With further characterisation, this relationship may yield therapeutic options in interferon-related pathologies.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12232707