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Editor | Xi's epidemiological research shows that Acute respiratory distress syndrome (ARDS) has become the main cause of death among patients with new coronavirus pneumonia
.
Acute respiratory distress syndrome is acute hypoxic respiratory insufficiency or failure caused by diffuse alveolar injury caused by inflammatory damage of lung capillary endothelial cells and alveolar epithelial cells during severe infection or trauma
.
Studies have shown that metformin, which has weight loss, anti-cancer, and anti-inflammatory functions, can significantly reduce COVID-19 mortality in patients with type 2 diabetes or obesity [1], but the specific mechanism is still unclear
.
On June 8, 2021, the Michael Karin research team of UCSD published an article Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation in Immunity, reporting that metformin inhibits NLRP3 inflammasome by blocking mitochondrial DNA synthesis Activate
.
Researchers treated LPS-induced ARDS mice with metformin and found that metformin significantly inhibited lung injury through pathological analysis
.
At the same time, in angiotensin-converting enzyme 2 (ACE2) transgenic mice, it was also observed that metformin significantly reduced the recruitment of macrophages and neutrophils, and blocked the apoptosis-related spots of adaptive molecules.
Aggregation of protein (ASC)
.
Therefore, researchers began to conduct further research on the mechanism of this phenotypic phenomenon
.
ASC is an important indicator of NLRP3 inflammasome
.
NLRP3 inflammasome is composed of nucleotide-binding oligomerization domain receptor-3 (NLRP3) protein, adaptation molecule apoptosis-associated dot-like protein (ASC) and caspase-1 precursor ( pro-caspase-1), in which ASC mediates the connection and action between NLRP3 and caspase-1 (caspase-1)
.
NLRP3 inflammasome mediates the release of cytokines in two key stages: Signal 1 (priming step): Toll-like receptor (TLR) ligand (such as lipopolysaccharide LPS) binds to its cognate receptor resulting in transcription factor NF- κB translocates to the nucleus, and then induces the expression of NLRP3, interleukin-1β (IL-1β) and interleukin-18 (IL-18) precursors (pro-IL-1β and pro-IL-18); signal 2 (activation step) ): The protein is responsible for the recognition of pathogen-related pattern molecules (PAMPs) or damage-related pattern molecules (DAMPs) to activate NLRP3 inflammasomes and cause the aggregation and cleavage of pro-caspase-1, thereby generating mature caspase-1, leading to pro-IL -1β and pro-IL-18 are cleaved to produce inflammatory factors IL-1β and IL-18 [2]
.
Studies have confirmed that IL-1β and IL-18 release play an important role in ARDS
.
Consistent with in vivo experiments, in vitro experiments with macrophages showed that metformin inhibited the lysis and release of caspase-1 and IL-1β
.
Interestingly, metformin does not affect the translocation of NF-κB to the nucleus, and the expression of NLRP3 and IL-1β precursor (pro-IL-1β)
.
Therefore, it is inferred that this may be related to the activation step that relies on mitochondrial DNA (mtDNA) synthesis
.
Michael Karin's team has reported that Toll-like receptors are involved in LPS-induced mtDNA synthesis, which is essential for NLRP3 signaling [3]
.
Through in vitro experiments, the researchers further found that as an inhibitor of mitochondrial Complex I, metformin inhibits ATP synthesis, thereby weakening the activity of mtDNA synthetase polg, thereby blocking the new synthesis of mtDNA
.
The newly synthesized naked mtDNA is easily oxidized in the mitochondria to generate Ox-mtDNA and then released into the cytoplasm to activate the NLRP3 inflammasome [4]
.
Therefore, in terms of mechanism, the researchers found that metformin inhibits the activation of NLRP3 inflammasomes by attenuating Ox-mtDNA in the cytoplasm, and inhibits the lysis and release of caspase-1 and IL-1β
.
This process does not depend on the AMPK pathway activated by metformin, autophagy or mitochondrial autophagy
.
On the other hand, in the LPS-induced ARDS mouse model, researchers found that metformin inhibited the expression and release of interleukin-6 (IL-6) inflammatory factors
.
Interleukin-6 (IL-6) is a key cytokine that promotes the "cytokine storm" caused by COVID-19
.
The regulation of IL-6 by metformin has prompted researchers to continue to explore its mechanism of action
.
As mentioned earlier, researchers have not found that metformin can regulate the translocation of NF-κB to the nucleus and the transcriptional regulation of typical NF-κB downstream genes, that is, this is the regulation of IL-6 expression independent of the NF-κB pathway
.
Through Chromatin Immunoprecipitation (CHIP), the researchers further discovered that metformin regulates the entry of the downstream transcription factor C/EBPβ into the nucleus by blocking the P38/JNK pathway to attenuate the IL-6 gene expression activity.
This regulation does not depend on the NLRP3 inflammasome, but the expression of IL-6 is at the level of mRNA transcription
.
In general, the study explained the specific mechanism of action of metformin in anti-inflammatory and alleviating acute respiratory distress syndrome (ARDS), discussed the rationality of metformin in the adjuvant treatment of COVID-19, and speculated that the use of metformin may prevent or inhibit ARDS Happen
.
Of course, the application value of metformin in patients with COVID-19 pneumonia still needs to be further confirmed by conducting more clinical trials
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
05.
004.
Plate maker: XI References 1.
Cheng, X.
, et al.
, Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality , in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.
Cell Metab, 2020.
32(4): p.
537-547 e3.
2.
Swanson, KV, M.
Deng, and JP Ting, The NLRP3 inflammasome: molecular activation and regulation to therapeutics.
Nat Rev Immunol, 2019.
19(8): p.
477-489.
3.
Zhong, Z.
, et al.
, New mitochondrial DNA synthesis enables NLRP3 inflammasome activation.
Nature, 2018.
560(7717) : p.
198-203.
4.
Shimada, K.
, et al.
, Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
Immunity, 2012.
36(3): p.
401-14.
Note for reprinting [Non-original article] Copyright of this article Owned by the author of the article, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated
.
.
Acute respiratory distress syndrome is acute hypoxic respiratory insufficiency or failure caused by diffuse alveolar injury caused by inflammatory damage of lung capillary endothelial cells and alveolar epithelial cells during severe infection or trauma
.
Studies have shown that metformin, which has weight loss, anti-cancer, and anti-inflammatory functions, can significantly reduce COVID-19 mortality in patients with type 2 diabetes or obesity [1], but the specific mechanism is still unclear
.
On June 8, 2021, the Michael Karin research team of UCSD published an article Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation in Immunity, reporting that metformin inhibits NLRP3 inflammasome by blocking mitochondrial DNA synthesis Activate
.
Researchers treated LPS-induced ARDS mice with metformin and found that metformin significantly inhibited lung injury through pathological analysis
.
At the same time, in angiotensin-converting enzyme 2 (ACE2) transgenic mice, it was also observed that metformin significantly reduced the recruitment of macrophages and neutrophils, and blocked the apoptosis-related spots of adaptive molecules.
Aggregation of protein (ASC)
.
Therefore, researchers began to conduct further research on the mechanism of this phenotypic phenomenon
.
ASC is an important indicator of NLRP3 inflammasome
.
NLRP3 inflammasome is composed of nucleotide-binding oligomerization domain receptor-3 (NLRP3) protein, adaptation molecule apoptosis-associated dot-like protein (ASC) and caspase-1 precursor ( pro-caspase-1), in which ASC mediates the connection and action between NLRP3 and caspase-1 (caspase-1)
.
NLRP3 inflammasome mediates the release of cytokines in two key stages: Signal 1 (priming step): Toll-like receptor (TLR) ligand (such as lipopolysaccharide LPS) binds to its cognate receptor resulting in transcription factor NF- κB translocates to the nucleus, and then induces the expression of NLRP3, interleukin-1β (IL-1β) and interleukin-18 (IL-18) precursors (pro-IL-1β and pro-IL-18); signal 2 (activation step) ): The protein is responsible for the recognition of pathogen-related pattern molecules (PAMPs) or damage-related pattern molecules (DAMPs) to activate NLRP3 inflammasomes and cause the aggregation and cleavage of pro-caspase-1, thereby generating mature caspase-1, leading to pro-IL -1β and pro-IL-18 are cleaved to produce inflammatory factors IL-1β and IL-18 [2]
.
Studies have confirmed that IL-1β and IL-18 release play an important role in ARDS
.
Consistent with in vivo experiments, in vitro experiments with macrophages showed that metformin inhibited the lysis and release of caspase-1 and IL-1β
.
Interestingly, metformin does not affect the translocation of NF-κB to the nucleus, and the expression of NLRP3 and IL-1β precursor (pro-IL-1β)
.
Therefore, it is inferred that this may be related to the activation step that relies on mitochondrial DNA (mtDNA) synthesis
.
Michael Karin's team has reported that Toll-like receptors are involved in LPS-induced mtDNA synthesis, which is essential for NLRP3 signaling [3]
.
Through in vitro experiments, the researchers further found that as an inhibitor of mitochondrial Complex I, metformin inhibits ATP synthesis, thereby weakening the activity of mtDNA synthetase polg, thereby blocking the new synthesis of mtDNA
.
The newly synthesized naked mtDNA is easily oxidized in the mitochondria to generate Ox-mtDNA and then released into the cytoplasm to activate the NLRP3 inflammasome [4]
.
Therefore, in terms of mechanism, the researchers found that metformin inhibits the activation of NLRP3 inflammasomes by attenuating Ox-mtDNA in the cytoplasm, and inhibits the lysis and release of caspase-1 and IL-1β
.
This process does not depend on the AMPK pathway activated by metformin, autophagy or mitochondrial autophagy
.
On the other hand, in the LPS-induced ARDS mouse model, researchers found that metformin inhibited the expression and release of interleukin-6 (IL-6) inflammatory factors
.
Interleukin-6 (IL-6) is a key cytokine that promotes the "cytokine storm" caused by COVID-19
.
The regulation of IL-6 by metformin has prompted researchers to continue to explore its mechanism of action
.
As mentioned earlier, researchers have not found that metformin can regulate the translocation of NF-κB to the nucleus and the transcriptional regulation of typical NF-κB downstream genes, that is, this is the regulation of IL-6 expression independent of the NF-κB pathway
.
Through Chromatin Immunoprecipitation (CHIP), the researchers further discovered that metformin regulates the entry of the downstream transcription factor C/EBPβ into the nucleus by blocking the P38/JNK pathway to attenuate the IL-6 gene expression activity.
This regulation does not depend on the NLRP3 inflammasome, but the expression of IL-6 is at the level of mRNA transcription
.
In general, the study explained the specific mechanism of action of metformin in anti-inflammatory and alleviating acute respiratory distress syndrome (ARDS), discussed the rationality of metformin in the adjuvant treatment of COVID-19, and speculated that the use of metformin may prevent or inhibit ARDS Happen
.
Of course, the application value of metformin in patients with COVID-19 pneumonia still needs to be further confirmed by conducting more clinical trials
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
05.
004.
Plate maker: XI References 1.
Cheng, X.
, et al.
, Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality , in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.
Cell Metab, 2020.
32(4): p.
537-547 e3.
2.
Swanson, KV, M.
Deng, and JP Ting, The NLRP3 inflammasome: molecular activation and regulation to therapeutics.
Nat Rev Immunol, 2019.
19(8): p.
477-489.
3.
Zhong, Z.
, et al.
, New mitochondrial DNA synthesis enables NLRP3 inflammasome activation.
Nature, 2018.
560(7717) : p.
198-203.
4.
Shimada, K.
, et al.
, Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
Immunity, 2012.
36(3): p.
401-14.
Note for reprinting [Non-original article] Copyright of this article Owned by the author of the article, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated
.
