HSF1 Protects Sepsis-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Shi, Xueyan; Li, Tao; Liu, Yanting; Yin, Leijin; Xiao, Lanbo; Fu, Liyao; Zhu, Yaxi; Chen, Huan; Wang, Kangkai; Xiao, Xianzhong; Zhang, Huali; Tan, Sichuang; Tan, Seang‐Lin

doi:10.3389/fimmu.2022.781003

Cited by 20 publications

(14 citation statements)

References 42 publications

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“…These results illustrate that TREM-1 activation promotes NLRP3 inflammasome priming. Caspase-1 p10 and caspase-1 p10 cleave pro-IL-1β into IL-1β p17, biomarkers for NLRP3 inflammasome activation 33 . We found that caspase-1 p10 and IL-1β p17 secretion were markedly induced by TREM-1 activation in the supernatant ( Figure 3 H-J ).…”

Section: Resultsmentioning

confidence: 99%

TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

Zhong¹,

Liu²,

Yang³

et al. 2023

Int. J. Biol. Sci.

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The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRRand pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1α (HIF-1α) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1α accumulation and translocation to the nucleus via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Inhibiting mTOR or HIF-1α also suppressed TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. Overall, the mTOR/HIF-1α/glycolysis pathway is a novel mechanism underlying TREM-1-governed NLRP3 inflammasome activation. Therapeutic targeting of the mTOR/HIF-1α/glycolysis pathway in TREM-1-activated macrophages could be beneficial for treating or preventing inflammatory diseases, such as ALI.

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Section: Resultsmentioning

confidence: 99%

TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

Zhong¹,

Liu²,

Yang³

et al. 2023

Int. J. Biol. Sci.

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“…HSF1 could indirectly control the expression of NLRP3 by activating Snail and regulating the TRX1/TXNIP and TRX1/ASK1 complexes or promoting β-catenin translocation from the cytoplasm to the nucleus, which inhibits XBP1 activation in response to TLR/TRAF6 stimulation in macrophages by enhancing βcatenin transcriptional activity [50,77]. Our recent research proved that HSF1 was involved in the activation of the NLRP3 inflammasome in septic acute lung injury (ALI) [81]. We proved that HSF1 could suppress NLRP3 inflammasome activation in transcriptional and posttranslational modification levels and that HSF1 can inhibit caspase1 activation and IL-1β maturation via inhibiting the NLRP3 pathway [81].…”

Section: Discussionmentioning

confidence: 99%

“…Our recent research proved that HSF1 was involved in the activation of the NLRP3 inflammasome in septic acute lung injury (ALI) [81]. We proved that HSF1 could suppress NLRP3 inflammasome activation in transcriptional and posttranslational modification levels and that HSF1 can inhibit caspase1 activation and IL-1β maturation via inhibiting the NLRP3 pathway [81]. This work supports previous results and indicates that HSF1 prevents brain injury from sepsis by inhibiting the sepsis-induced pyroptosis through the NLRP3-dependent caspase1/IL-1β pathway.…”

Section: Discussionmentioning

confidence: 99%

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

et al. 2023

Mediators of Inflammation

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Background. Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient’s prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective. NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods. In this study, we used wild-type mice and hsf1-/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results. The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1-/- mouse model compared to hsf1+/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion. These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

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“…Western blotting analysis and quantitative real-time PCR were performed as described previously (40). The mtDNA copy number was quantified through determining the mtDNA/nDNA (ND1/18S) ratio as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

Nucleolin Promotes Autophagy Through PGC-1α in LPS-Induced Myocardial Injury

Yin¹,

Yuan²,

Tang³

et al. 2023

Shock

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As a multifunctional protein, nucleolin can participate in a variety of cellular processes. Nucleolin also has multiple protective effects on heart disease. Previous studies have shown that nucleolin could not only resist oxidative stress damage and inflammatory damage, but also regulate autophagy to play a protective role in cardiac ischemia. However, the specific mechanism has not been fully elucidated in LPS-induced myocardial injury. Therefore, the aim of this study is to explore the underlying mechanism by which nucleolin regulates autophagy to protect against LPS-induced myocardial injury in vivo and in vitro. In our study, we found that nucleolin could bind to PGC-1α, and we predicted that this interaction could promote autophagy and played a role in inhibiting cardiomyocyte apoptosis. Downregulation of nucleolin in H9C2 cells resulted in decreased autophagy and increased cell apoptosis during LPS-induced myocardial injury, while upregulation of PGC-1α had the opposite protective effect. Upregulation of nucleolin expression in cardiomyocytes could increase the level of autophagy during LPS-induced myocardial injury. In contrast, interference with PGC-1α expression resulted in a decrease in the protective effect of nucleolin, leading to reduced autophagy and thus increasing apoptosis. By using tandem fluorescent-tagged LC3 autophagic flux detection system, we observed autophagic flux and determined that PGC-1α interference could block autophagic lysosomal progression. We further tested our hypothesis in the nucleolin cardiac-specific knockout mice. Finally, we also found that inhibition of autophagy can reduce mitochondrial biogenesis as well as increase apoptosis, which demonstrated the importance of autophagy. Therefore, we can speculate that nucleolin can protect LPS-induced myocardial injury by regulating autophagy, and this protective effect may be mediated by the interaction with PGC-1α, which can positively regulate the ULK1, an autophagy-related protein. Our study provides a new clue for the cardioprotective effect of nucleolin, and may provide new evidence for the treatment of LPS-induced myocardial injury through the regulation of autophagy.

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HSF1 Protects Sepsis-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome Activation

Cited by 20 publications

References 42 publications

TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

Nucleolin Promotes Autophagy Through PGC-1α in LPS-Induced Myocardial Injury

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