STING mediates SU5416/hypoxia-induced pulmonary arterial hypertension in rats by regulating macrophage NLRP3 inflammasome activation

Wu, Dandan; Yan, Deyue; Liao, Juan; Xie, Shanshan; Meng, Hui; Lan, Wei‐Fang

doi:10.1016/j.imbio.2023.152345

Cited by 10 publications

(4 citation statements)

References 57 publications

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“…We found that pharmacological inhibition of STING with H-151 administration had a therapeutic effect on the development of PH in both prophylactic and therapeutic models by decreasing interferon signaling. Consistent with our findings, recently study found that pharmacological inhibition of STING with C-176 prevented the development of PH in rat SuHx model through reducing the activation of inflammasome and proinflammatory cytokines in macrophages (43). STING is ubiquitously expressed in a wide range of cells, such as macrophages, T cells and smooth muscle cells.…”

Section: Discussionsupporting

confidence: 91%

STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3

Deng,

Cao,

Cai

et al. 2024

Preprint

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Rational/ObjectivesPulmonary hypertension (PH) is an incurable disease characterized by pulmonary arterial remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH.MethodsPH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis.Measurement and Main ResultsThe cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and the TNF-α induced PAECsin vitro. In particular, STING significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling bothin vitroandin vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/ interferon-stimulated genes (ISGs) was observedin vivo.ConclusionsOur findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

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Section: Discussionsupporting

confidence: 91%

STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3

Deng,

Cao,

Cai

et al. 2024

Preprint

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“…M1 macrophage infiltration in the right ventricle with enhanced NOD-like receptor thermal protein domain associated protein 3 (NLRP3) expression and activation results in right heart dysfunction [ 43 ]. Stimulators of interferon genes in macrophages induce PH progression via the activation of NLRP3 signalling transduction [ 77 ]. Moreover, prostaglandin D2 released by macrophages inhibits smooth muscle cell proliferation and induces vasodilation [ 78 ].…”

Section: Introductionmentioning

confidence: 99%

Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension

Zuo,

Li,

Gao

et al. 2024

Respir Res

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Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. Recent advances suggest that macrophages coordinate interactions among different proinflammatory and anti-inflammatory mediators, and other cellular components such as smooth muscle cells and fibroblasts. In this review, we summarize the current literature on the role of macrophages in the pathogenesis of pulmonary hypertension, including the origin of pulmonary macrophages and their response to triggers of pulmonary hypertension. We then discuss the interactions among macrophages, cytokines, and vascular adventitial fibroblasts in pulmonary hypertension, as well as the potential therapeutic benefits of macrophages in this disease. Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management.

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“…These in ammatory cytokines induce pulmonary interstitial brosis and pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis and ultimately lead to the occurrence of PAH (13)(14)(15)(16). We have reported that there is speci c activation of NLRP3 in macrophages and that inhibition of NLRP3 can improve the progression of PAH (17)(18)(19). Therefore, blocking the reprogramming of glucose metabolism can effectively inhibit the in ammatory response.…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signaling pathways mediate monocrotaline-induced pulmonary arterial hypertension via glycolysis in rats

Meng,

Deng,

Liao

et al. 2023

Preprint

Self Cite

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Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Metabolic abnormalities and immune inflammation are deeply involved in pulmonary vascular remodeling and in the formation of PAH. Cumulative evidence indicates that β-catenin and abnormal glucose metabolism play an important role in the development of PAH, but the underlying mechanism is still elusive. To elucidate this mechanism, we first established a rat model of PAH and then treated some rats with a specific β-catenin inhibitor (XAV939). After examining the protein expression of β-catenin, levels of indicators of glucose metabolism, right ventricular pressure (RVSP) and pulmonary artery histopathology, we found that monocrotaline (MCT)-exposed rats had an increase in levels of glycolytic metabolism markers and that this phenomenon could be blocked by β-catenin inhibitors. This study demonstrated that Wnt/β-catenin signaling promotes the inflammatory response involved in pulmonary vascular remodeling and participates in the formation of PAH by regulating glycolysis in macrophages. Inhibition of Wnt/β-catenin signaling pathways could improve the progression of PAH, which may provide novel therapeutic targets for the treatment of PAH.

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STING mediates SU5416/hypoxia-induced pulmonary arterial hypertension in rats by regulating macrophage NLRP3 inflammasome activation

Cited by 10 publications

References 57 publications

STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3

STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3

Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension

Wnt/β-catenin signaling pathways mediate monocrotaline-induced pulmonary arterial hypertension via glycolysis in rats

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