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

  • Sci Rep. 2022 Oct 24;12(1):17827. doi: 10.1038/s41598-022-20519-7.
Dieter Kabelitz  1 ,  Michal Zarobkiewicz  2  3 ,  Michelle Heib  2 ,  Ruben Serrano  2  4 ,  Monika Kunz  2 ,  Guranda Chitadze  5 ,  Dieter Adam  2 ,  Christian Peters  2
Affiliations
  • 1. Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany. [email protected].
  • 2. Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany.
  • 3. Department of Clinical Immunology, Medical University of Lublin, 20-093, Lublin, Poland.
  • 4. Institute of Immunology, Medical University Hannover, 30625, Hannover, Germany.
  • 5. Unit for Hematological Diagnostics, Department of Internal Medicine II, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
PMID: 36280676 DOI: 10.1038/s41598-022-20519-7
Abstract

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 μM 2'3'c-GAMP, 100 nM diABZI, 25 μM MSA-2) induced IFN-β, IP-10, and large amounts of IL-1β and TNF-α, 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-1β and TNF-α were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 μM) 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-1β and TNF-α. 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.

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