Cells (Nov 2023)

C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages

  • Oliver Wright,
  • Anna Harris,
  • Van Dien Nguyen,
  • You Zhou,
  • Maxim Durand,
  • Abbie Jayyaratnam,
  • Darren Gormley,
  • Luke A. J. O’Neill,
  • Kathy Triantafilou,
  • Eva Maria Nichols,
  • Lee M. Booty

DOI
https://doi.org/10.3390/cells12232707
Journal volume & issue
Vol. 12, no. 23
p. 2707

Abstract

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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.

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