Objective:The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon(IFN)genes(STING)signaling pathway has been implicated in the initiation and maintenance of a variety of inflammatory diseases.Thus,the search for mo...Objective:The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon(IFN)genes(STING)signaling pathway has been implicated in the initiation and maintenance of a variety of inflammatory diseases.Thus,the search for modulators of the cGAS-STING signaling pathway is likely to contribute to their therapeutic prevention and treatment.Natural products from traditional Chinese medicine are an important source for modern drug development;digitoflavone(DG),a natural flavonoid present in a variety of plants,has been shown to have anti-inflammatory effects.However,its specific mechanisms of action remain unclear and have yet to be used in clinical settings.Materials and Methods:The activation of the cGAS-STING pathway was modeled in bone marrow-derived macrophages(BMDMs)and human leukemia monocytic cell line(THP-1)cells in vivo,and the expression of type I IFN-related genes and pro-inflammatory cytokines was detected after DG pretreatment.Next,we examined the effect of DG on STING downstream signaling events,such as STING oligomerization and functional STING signalosome formation.Using in vivo experiments,the 5,6-dimethylxanthenone-4-acetic acid(DMXAA)-induced agonist and lipopolysaccharide-induced acute lung injury models were used to assay the therapeutic effects of DG.Results:DG effectively inhibited the activation of the cGAS-STING signaling pathway,which was accompanied by an increase in the levels of type I IFN and pro-inflammatory cytokines in BMDMs and THP-1 cells.DG did not affect STING oligomerization but inhibited STING-Interferon Regulatory Factor 3(IRF3)or TANK-binding kinase 1-IRF3 binding.In addition,DG inhibited the activation of the cGAS-STING pathway induced by DMXAA in vivo,while demonstrating favorable therapeutic effects on acute lung injury.Conclusions:Our results suggest that DG is an inhibitor of the cGAS-STING signaling pathway,which may act by affecting the formation of functional STING signaling pathways.Moreover,the ameliorative effect of DG on acute lung injury could be used to treat cGAS-STING pathway-mediated inflammatory diseases.展开更多
基金funded by the National Natural Science Foundation of China under the Joint Fund Key Project(U23A20519)the Natural Science Foundation of Beijing,China(grant no.7232321)+1 种基金the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(no.ZYYCXTD-C-202005)the National Natural Science Foundation of China(grant no.81721002)。
文摘Objective:The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon(IFN)genes(STING)signaling pathway has been implicated in the initiation and maintenance of a variety of inflammatory diseases.Thus,the search for modulators of the cGAS-STING signaling pathway is likely to contribute to their therapeutic prevention and treatment.Natural products from traditional Chinese medicine are an important source for modern drug development;digitoflavone(DG),a natural flavonoid present in a variety of plants,has been shown to have anti-inflammatory effects.However,its specific mechanisms of action remain unclear and have yet to be used in clinical settings.Materials and Methods:The activation of the cGAS-STING pathway was modeled in bone marrow-derived macrophages(BMDMs)and human leukemia monocytic cell line(THP-1)cells in vivo,and the expression of type I IFN-related genes and pro-inflammatory cytokines was detected after DG pretreatment.Next,we examined the effect of DG on STING downstream signaling events,such as STING oligomerization and functional STING signalosome formation.Using in vivo experiments,the 5,6-dimethylxanthenone-4-acetic acid(DMXAA)-induced agonist and lipopolysaccharide-induced acute lung injury models were used to assay the therapeutic effects of DG.Results:DG effectively inhibited the activation of the cGAS-STING signaling pathway,which was accompanied by an increase in the levels of type I IFN and pro-inflammatory cytokines in BMDMs and THP-1 cells.DG did not affect STING oligomerization but inhibited STING-Interferon Regulatory Factor 3(IRF3)or TANK-binding kinase 1-IRF3 binding.In addition,DG inhibited the activation of the cGAS-STING pathway induced by DMXAA in vivo,while demonstrating favorable therapeutic effects on acute lung injury.Conclusions:Our results suggest that DG is an inhibitor of the cGAS-STING signaling pathway,which may act by affecting the formation of functional STING signaling pathways.Moreover,the ameliorative effect of DG on acute lung injury could be used to treat cGAS-STING pathway-mediated inflammatory diseases.
