Noncanonical IRF3 function mediates STING-dependent pro-inflammatory cytokine production in macrophages

STING is an important component in the host innate immune system where its activation by cyclic dinucleotides culminates in the production of interferons and pro-inflammatory cytokines that mediate host defence against infection. While the mechanisms that govern STING-induced interferon production have been comprehensively characterised, how pro-inflammatory cytokines are produced downstream of STING remains less understood. Here we discover that IRF3 is critical for effective STING-mediated inflammatory cytokine production from macrophages as those lacking IRF3 display significant defects. Interestingly, the loss of IRF3 does not impact the activation of the prominent pro-inflammatory transcription factor, NF-κB, but rather affects the AP-1 transcriptional complex. We further discover the role of IRF3 in STING inflammatory responses is independent of its phosphorylation and distinct from its role as a transcription factor for induction of type I interferons. This additional activity of IRF3 is dependent on its recruitment to the previously defined IRF3 binding motif within the C-terminal tail of STING. Hence, our findings reveal an unexpected noncanonical function of IRF3 that is critical for mediating STING-induced pro-inflammatory cytokines from macrophages.