Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is a cytosolic sensor of microbial and host-derived DNA and plays a key role in innate immunity. Activation of STING by cyclic dinucleotide (CDN) ligands in human monocytes induces a type I interferon response and production of pro-inflammatory cytokines associated with the induction of massive cell death. In this study we have re-evaluated the effect of signal strength of STING activation on the cytokine plasticity of human monocytes. CDN (2 ' 3 ' c-GAMP) and non-CDN (diABZI, MSA-2) STING ligands in the range of EC50 concentrations (15 mu M 2 ' 3 ' c-GAMP, 100 nM diABZI, 25 mu M MSA-2) induced IFN-beta, IP-10, and large amounts of IL-1 beta and TNF-alpha, but no IL-10 or IL-19. Interestingly, LPS-induced production of IL-10 and IL-19 was abolished in the presence of diABZI or MSA-2, whereas IL-1 beta and TNF-alpha were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 mu M) or 100-fold lower (diABZI, i.e. 1 nM) concentrations strongly stimulated secretion of anti-inflammatory IL-10 and IL-19, but little of IL-1 beta and TNF-alpha. Induction of IL-10 was associated with up-regulation of PRDM1 (Blimp-1). While cytokine secretion stimulated by the higher concentrations was accompanied by apoptosis as shown by cleavage of caspase-3 and PARP-1, the low concentrations did not trigger overt cell death yet induced cleavage of gasdermin-D. Our results reveal a previously unrecognized plasticity of human monocytes in their signal strength-dependent production of pro- versus anti-inflammatory cytokines upon STING activation.

Automated summary

This study reveals the influence of signal strength on the cytokine plasticity of human monocytes upon STING activation. Higher concentrations of ligands induce pro-inflammatory cytokines, while lower concentrations stimulate the secretion of anti-inflammatory cytokines.