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C5aR2 regulates STING-mediated interferon beta production in human macrophages

Wright, Oliver, Harris, Anna, Nguyen, Van Dien, Zhou, You ORCID:, Durand, Maxim, Jayyaratnam, Abbie, Gormley, Darren, O?Neill, Luke A. J., Triantafilou, Kathy, Nichols, Eva Maria and Booty, Lee M. 2023. C5aR2 regulates STING-mediated interferon beta production in human macrophages. Cells 12 (23) , 2707. 10.3390/cells12232707

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: MDPI
ISSN: 2073-4409
Date of First Compliant Deposit: 30 November 2023
Date of Acceptance: 23 November 2023
Last Modified: 30 Nov 2023 11:15

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