RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis

Abstract

Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT‐29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL‐mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro‐necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA‐induced intestinal injury and sepsis. Conclusions These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING‐driven inflammatory diseases.

Mediators of necroptosis: from cell death to metabolic regulation

“…Since many of the small molecule inhibitors in the necroptotic pathway have resulted in activation of other cell death pathways, some investigators have suggested that targeting necroptosis response and/or interacting pathways, rather than directly targeting the mediators of necroptosis, may be a more fruitful strategy (Vucur et al, 2023 ; Zhang et al, 2023b ). For example, Vucur and colleagues demonstrated that inhibition of NF-кB limited RIPK3-mediated immune responses in a model of liver cancer and prevented cancer progression (Vucur et al, 2023 ).…”

“…For example, Vucur and colleagues demonstrated that inhibition of NF-кB limited RIPK3-mediated immune responses in a model of liver cancer and prevented cancer progression (Vucur et al, 2023 ). STING inhibitors have also been suggested as a potential mechanism to target necroptotic signaling in models of sepsis, due to the interactions between these two signaling pathways (Zhang et al, 2023b ).…”

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

“…Activation of necroptosis by RIPK3 or MLKL in macrophages is dependent on DNA sensing and is elevated in autoimmune conditions like systemic lupus erythematosus (SLE) [126]. Necroptotic signaling stimulates STING, whereas suppression of RIPK3 inhibits STING by redirecting STING to autophagosomes [127]. In mouse models, STING agonists induce necroptosis in primary macrophages in vitro in a STING and RIPK3dependent pathway linked to production of and IFN and TNF [128].…”