Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury

Yang, Huihui; Jiang, Huiling; Tao, Jia‐Hao; Zhang, Chenyu; Xiong, Jian‐Bing; Yang, Jin‐Tong; Liu, Yu-Biao; Zhong, Wenjing; Guan, Xin‐Xin; Duan, Jia‐Xi; Zhang, Yanfeng; Liu, Shao-Kun; Jiang, Jianxin; Zhou, Yong; Guan, Cha Xiang

doi:10.1038/s12276-022-00889-8

Cited by 33 publications

(32 citation statements)

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“…To sum up, RIPK1-RIPK3-MLKL signaling cascade triggers necroptosis. 8,15,25 In 2004, necroptosis has been implicated in bronchoalveolar fluid (BALF) of ALI patients. 26 In high-dosed lipopolysaccharide (LPS)-induced ARDS animal models, increased phosphorylated RIPK3 and MLKL were demonstrated.…”

Section: Introductionmentioning

confidence: 99%

“…It is reported that necroptosis, a new form of regulated cell deaths (RCDs), plays a role in the pathogenesis of ALI/ARDS. ,, Necroptosis, first defined by Yuan group, can be activated in a wide range of human inflammatory-involved diseases. − Mechanism of necroptosis has been relatively clear by numerous efforts in the past 2 decades . Various death receptors, such as TNF receptor-1 (TNFR1), CD95 (Fas), interferons (IFNs), and IFN-induced Z-DNA binding protein 1 (ZBP1), could initiate necroptosis pathway. − Briefly exemplified by TNFR1, tumor necrosis factor-α (TNF-α) interacts with TNFR1 to form signaling complex I on the membrane .…”

Section: Introductionmentioning

confidence: 99%

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Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

et al. 2023

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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and SZM-1209 showed high anti-necroptotic activity (EC50 = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 (K d,RIPK1 = 85 nM, K d,RIPK3 > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, SZM-1209 could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, SZM-1209 significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of SZM-1209 against RIPK1, necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

et al. 2023

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“…Necroptosis results in the disrupture of the cellular membrane and the release of components, including DAMPs and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which can cause a self-amplified inflammatory process [ 13 ]. Our recent studies found that L‐OPA1 deficiency and mitochondrial citrate accumulation mediate mitochondrial fission, induce necroptosis of alveolar epithelial cells, and exacerbate ALI [ 10 , 14 ]. For macrophages, the human respiratory syncytial virus (RSV) induces necroptosis of macrophages, aggravating pneumonia [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury

et al. 2023

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Background Necroptosis of macrophages is a necessary element in reinforcing intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that sparks macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The influence of TREM-1 on the destiny of macrophages in ALI requires further investigation. Methods TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Macrophages were treated with GSK872 (a RIPK3 inhibitor), Mdivi-1 (a DRP1 inhibitor), or Rapamycin (an mTOR inhibitor) to investigate whether TREM-1 could induce necroptosis in macrophages, and the mechanism of this process. Results We first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. We discovered that mTOR had a previously unrecognized function in modulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation through mTOR signaling, which in turn caused surplus mitochondrial fission-mediated necroptosis of macrophages, consequently exacerbating ALI. Conclusion In this study, we reported that TREM-1 acted as a necroptotic stimulus of AlvMs, fueling inflammation and aggravating ALI. We also provided compelling evidence suggesting that mTOR-dependent mitochondrial fission is the underpinning of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.

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“…Necroptosis leads to the rupture of the cell membrane and the release of various intracellular components, including DAMPs and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), to self-amplify or even trigger the inflammatory process [12]. Our recent studies found that L-OPA1 deficiency and mitochondrial citrate accumulation mediate mitochondrial fission, induce necroptosis of alveolar epithelial cells, and exacerbate ALI [9,13]. For macrophages, the human respiratory syncytial virus (RSV) induces necroptosis of macrophages, aggravating pneumonia [14].…”

Section: Introductionmentioning

confidence: 99%

“…Excessive mitophagy is maladaptive and associated with cell death [30]. Recently, we have reported that excessive mitochondrial fission induced by mitochondrial citrate accumulation contributes to necroptosis by triggering mitophagy in alveolar epithelial cells [13]. Thus, mitochondrial fission would be a key mechanism triggering necroptosis.…”

Section: Introductionmentioning

confidence: 99%

TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury

Zhong

Zhang

Duan

et al. 2023

Preprint

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Background Necroptosis of macrophage plays an essential role in amplifying intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that triggers macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The role of TREM-1 in macrophage fate during ALI needs further investigation. Methods TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Mechanistically, macrophages were treated with RIPK3 inhibitor (GSK872), GTPase dynamin-related protein 1 (DRP1) inhibitor (Mdivi-1), or the nutrient-sensing mechanistic/mammalian target of rapamycin complex (mTOR) inhibitor (Rapamycin) to investigate macrophage necroptosis induced by TREM-1. Results We first observed that blockade of TREM-1 attenuated macrophage necroptosis in LPS-induced ALI mice. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. Interestingly, we identified a previously unknown role of mTOR in regulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation via mTOR signaling, leading to excessive mitochondrial fission-mediated necroptosis of macrophages, and finally exacerbated ALI. Conclusion In this study, we reported TREM-1 acted as a necroptotic stimulus of macrophage, which fueled inflammation and aggravated ALI. We also provided compelling evidence suggesting mTOR-dependent mitochondrial fission as underpinnings of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.

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Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury

Cited by 33 publications

References 56 publications

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury

TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury

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