STING Agonist-Mediated Cytokine Secretion Is Accompanied by Monocyte Apoptosis

Polidarová, Markéta Pimková; Břehová, Petra; Dejmek, Milan; Birkuš, Gabriel; Brázdová, Andrea

doi:10.1021/acsinfecdis.1c00554

Cited by 9 publications

(30 citation statements)

References 33 publications

(118 reference statements)

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“…Taken together, our results observed with stimulation of purified monocytes with commonly used “normal” concentrations of STING ligands cGAMP, diABZI and MSA-2 are fully in line with previous research, i.e. our experiments confirm the reported potent stimulation of secretion of pro-inflammatory cytokines IL-1β and TNF-α associated with the simultaneous induction of massive apoptotic cell death 38 . Although Fas/CD95-dependent and spontaneous apoptosis of monocytes have been reported to induce the production of anti-inflammatory IL-10 in monocytes 39 , 40 , the STING-mediated apoptotic death did not trigger any IL-10 (and IL-19) secretion in our experiments, in line with the general assumption that the cGAS/STING pathway triggers type I IFN production via TBK1/IRF3 and pro-inflammatory cytokines via NF-κB 3 .…”

Section: Discussionsupporting

confidence: 92%

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

Kabelitz

Zarobkiewicz

Heib

et al. 2022

Sci Rep

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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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Section: Discussionsupporting

confidence: 92%

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

Kabelitz

Zarobkiewicz

Heib

et al. 2022

Sci Rep

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“…Accordingly, the gating of functional cells could be a useful approach in therapeutic studies (cancer, autoimmune diseases, etc.). Concerning data exportation and interpretation, the frequency of cell population in live cells can be used for monitoring the changes of immune subset ratios in various pathophysiological conditions [ 40 ]. In addition, the frequency of parent population is suitable for monitoring the expression of a particular marker within the population of interest.…”

Section: Expected Results and Discussionmentioning

confidence: 99%

Multiparametric Flow Cytometry-Based Immunophenotyping of Mouse Liver Immune Cells

Vaneková

Polidarová

Veverka

et al. 2022

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The liver is a complex organ that governs many types of metabolisms, including energy metabolism and other cellular processes. The liver also plays a crucial role in important functions in immunity, and the activity of liver tissue-associated immunity affects the outcome of many liver pathologies. A thorough characterization of the liver immune microenvironment may contribute to a better understanding of immune signaling, the mechanisms of specific immune responses, and even to improved predictions about therapy outcomes. In this paper, we present an optimized, simple, and rapid protocol to characterize the liver-associated immune cell milieu. We believe that the most suitable technique for obtaining a complex immune cell suspension and for removing contaminating blood cells is to perform mouse liver perfusion, using only phosphate buffer saline. Combining an enzymatic digestion and a mechanical dissociation of liver tissue, followed by cell purification, improves downstream applications. This combination is an essential prerequisite for immune cell determination and characterization. We then demonstrate a flow cytometry-based multiparametric immunophenotyping along with a gating strategy to detect and quantify liver endothelial cells, T cells (helper and cytotoxic), B cells, NK cells, NKT cells, neutrophils, monocytes (subsets included), dendritic cells (subsets included), macrophages and Kupffer cells.

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“…As LPS induces CD69 expression in T cells in vivo , antigen presence may be thus required . Overall, in vitro cytokine production by hNPCs in response to STING agonist treatment matched that of PBMCs . Furthermore, based on T cell activation, liver-targeted STING agonist treatment may be a viable therapeutic option.…”

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confidence: 83%

“…STING agonists potently stimulate human immune cells into producing cytokines with anticipated antiviral properties. , Yet, treating PHHs with STING agonists ( 1 – 3 ) failed to inhibit either HBV E or HBV S antigen secretion (HBe/HBsAg, Figure S1A). Nevertheless, these PHHs did not express STING under any condition analyzed in this study, as shown by immunoblotting (Figure S1B).…”

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confidence: 99%

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Synthetic Stimulator of Interferon Genes (STING) Agonists Induce a Cytokine-Mediated Anti-Hepatitis B Virus Response in Nonparenchymal Liver Cells

et al. 2022

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Chronic hepatitis B (CHB) remains a major public health problem worldwide, with limited treatment options, but inducing an antiviral response by innate immunity activation may provide a therapeutic alternative. We assessed the cytokine-mediated anti-hepatitis B virus (HBV) potential for stimulating the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway using STING agonists in primary human hepatocytes (PHH) and nonparenchymal liver cells (NPCs). The natural STING agonist, 2′,3′-cyclic GMP–AMP, the synthetic analogue 3′,3′-c-di(2′F,2′dAMP), and its bis(pivaloyloxymethyl) prodrug had strong indirect cytokine-mediated anti-HBV effects in PHH regardless of HBV genotype. Furthermore, STING agonists induced anti-HBV cytokine secretion in vitro, in both human and mouse NPCs, and triggered hepatic T cell activation. Cytokine secretion and lymphocyte activation were equally stimulated in NPCs isolated from control and HBV-persistent mice. Therefore, STING agonists modulate immune activation regardless of HBV persistence, paving the way toward a CHB therapy.

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STING Agonist-Mediated Cytokine Secretion Is Accompanied by Monocyte Apoptosis

Cited by 9 publications

References 33 publications

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

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

Multiparametric Flow Cytometry-Based Immunophenotyping of Mouse Liver Immune Cells

Synthetic Stimulator of Interferon Genes (STING) Agonists Induce a Cytokine-Mediated Anti-Hepatitis B Virus Response in Nonparenchymal Liver Cells

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