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Systemic lupus erythematosus (SLE) is a representative autoimmune disease characterized by loss of immune tolerance and abnormal activation of the immune system
.
The current traditional view believes that SLE is mainly caused by lymphocytes producing a large number of autoantibodies against self-antigens, which in turn causes disease
.
However, the role and mechanism of innate immune cells in SLE patients in the pathogenesis and progression of lupus still lack in-depth research
.
On August 12, 2021, Professor Zhang Xuan from the Clinical Immunology Center of Chinese Academy of Medical Sciences and Peking Union Medical College/Beijing Hospital led the research team and the collaborators of Harvard Medical School (together as doctoral students Li Pengchong, Li Ketian, and Jiang Mengdi) in the journal Nature Immunology Published an article on Glutathione peroxidase 4 regulated neutrophil ferroptosis induces systemic autoimmunity, with the lupus cohort covering Asian, Caucasian and African American races as the research object, with the help of in vivo and in vitro experiments, knockout gene models, transcriptomics, etc.
Means, for the first time proposed and discovered the key role of neutrophil iron death in human and mouse autoimmune diseases, and conducted an in-depth analysis of the regulatory mechanism that induces the specific form of neutrophil death in SLE patients
.
At the same time, a typical SLE animal model was established by simply intervening in neutrophil iron death
.
The far-reaching significance of this study is that it overturns the traditional concept that SLE is mainly caused by adaptive immune abnormalities, and confirms that innate immune cell abnormalities play a key role in systemic autoimmunity
.
Therefore, it will inevitably stimulate discussion in the academic community about the interaction between the innate and adaptive immune systems in maintaining immune homeostasis, and how specific perturbations of this interaction can lead to autoimmunity
.
At the same time, this study also opened up a new target direction for the treatment of SLE
.
Serum factors reduce SLE neutrophil activity.
SLE patients showed a significantly lower neutrophil count than healthy people and other immune diseases, and the cell viability rate was also significantly reduced.
The above phenomenon was significantly alleviated after treatment
.
The research team speculates that this phenomenon is related to serum, and tested the serum inflammatory factor profile of SLE patients, and found that the specifically elevated type I interferon in SLE can significantly induce neutrophil death, and blocking type I interferon can alleviate the SLE serum Induced cell death
.
The production of autoantibodies is an important feature of lupus.
The research team also found that the proportion of dsDNA antibodies in the IgG of lupus patients was significantly negatively correlated with the neutrophil count, and the isolated SLE IgG significantly promoted the death of neutrophils.
The ability of SLE serum containing IgG to induce the death of neutrophils is reduced
.
SLE neutrophils show the characteristics of iron death.
In order to study the specific forms of death of neutrophils, the research team observed the morphology of SLE neutrophils through electron microscopy and found that their mitochondria showed the characteristics of iron death.
Further verification also showed that SLE The content of lipid-ROS (lipid-ROS) in neutrophils was significantly higher than that of healthy controls.
Anti-iron death drugs can block the effect of SLE serum on neutrophil death
.
At the same time, type I interferon and SLE IgG can significantly induce iron death of neutrophils
.
It is worth noting that the research team found that the process of neutrophil extracellular capture network (NETosis) is not the main death form of lupus neutrophils
.
Inhibition of iron death can slow down the progress of lupus mice.
The administration of iron death inhibitor Liproxstatin-1 can significantly alleviate the progress of lupus in MRL.
lpr mice.
Specific indicators include proteinuria, anti-dsDNA, reduction of inflammatory factor levels, spleen, and lymph nodes.
Shrinkage and restoration of complement C3
.
Autoantibodies and interferon reduce the expression of neutrophil GPX4.
The research team used neutrophil transcriptome sequencing and found that 23 iron death-related genes were abnormally expressed in patients with lupus, among which glutathione peroxidase 4 ( GPX4) was significantly reduced, and the degree of reduction was related to the activity of lupus disease, and recovered after treatment
.
The research team found that SLE serum can reduce the expression of GPX4, and blocking type I interferon or SLE IgG can alleviate the reduction of GPX4, and this phenomenon shows neutrophil specificity
.
Mice with specific neutrophil GPX4 haploid deficiency spontaneously developed lupus phenotypes.
Next, the research team constructed a mouse model of neutrophil GPX4 knockdown and found that the model spontaneously developed lupus phenotypes, including skin lesions.
, Kidney immune complex deposition, anti-dsDNA and inflammatory factors increased, the mouse showed obvious spleen and lymph node enlargement at the age of 12 months, which better mimics the human lupus phenotype
.
CaMKIV-CREM-GPX4 pathway In order to study the specific mechanism of the decrease of neutrophil GPX4 and iron death in patients with lupus, the researchers used chromatin immunoprecipitation and DNA-pulldown methods to find the promoter of patient neutrophil GPX4 The abnormal binding of CREM-suppressed transcription factors, SLE serum, or type I interferon and SLE IgG can activate the CaMKIV molecule so that CREM binds to the promoter region of GPX4 and inhibits the transcription of GPX4
.
In Crem-/- and Camk4-/- lupus animal models, the decline of GPX4 was also significantly alleviated
.
In summary, the main new findings of the study are: 1.
There is obvious spontaneous iron death in neutrophils of patients with active SLE, and after effective treatment, cellular iron death returns to normal levels
.
2.
Serum autoreactive IgG and type I interferon can induce iron death of neutrophils
.
3.
Iron death inhibitors can significantly reduce the disease progression of lupus mice
.
4.
Mouse myeloid-specific haploid knockout of iron death negative regulatory protein GPX4 can induce a typical lupus-like phenotype
.
5.
Serum autoreactive IgG and type I interferon inhibit the expression of GPX4 in neutrophils of SLE patients through the CaMKIV/CREM pathway, leading to the accumulation of lipid reactive oxygen species in the cells and the iron death of neutrophils
.
Professor Zhang Xuan pointed out: “Past research mainly emphasized the role of adaptive immunity in inducing systemic autoimmune diseases.
Our research has subverted the traditional concept to some extent.
The abnormality of cells of the innate immune system can lead to the system the occurrence of autoimmunity
.
specifically, namely neutrophils GPX4 deficiency leads to typical SLE phenotype iron can occur after death
.
effect of previous iron death in autoimmune diseases not reported, our research shows that it is not only lupus An important reason for the reduction of white blood cells in patients, and it can induce a cascade of pathological reactions to promote the development of SLE
.
" Original link: https://doi.
org/10.
1038/s41590-021-00993-3 Non-original articles] The copyright of this article belongs to 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
.
.
The current traditional view believes that SLE is mainly caused by lymphocytes producing a large number of autoantibodies against self-antigens, which in turn causes disease
.
However, the role and mechanism of innate immune cells in SLE patients in the pathogenesis and progression of lupus still lack in-depth research
.
On August 12, 2021, Professor Zhang Xuan from the Clinical Immunology Center of Chinese Academy of Medical Sciences and Peking Union Medical College/Beijing Hospital led the research team and the collaborators of Harvard Medical School (together as doctoral students Li Pengchong, Li Ketian, and Jiang Mengdi) in the journal Nature Immunology Published an article on Glutathione peroxidase 4 regulated neutrophil ferroptosis induces systemic autoimmunity, with the lupus cohort covering Asian, Caucasian and African American races as the research object, with the help of in vivo and in vitro experiments, knockout gene models, transcriptomics, etc.
Means, for the first time proposed and discovered the key role of neutrophil iron death in human and mouse autoimmune diseases, and conducted an in-depth analysis of the regulatory mechanism that induces the specific form of neutrophil death in SLE patients
.
At the same time, a typical SLE animal model was established by simply intervening in neutrophil iron death
.
The far-reaching significance of this study is that it overturns the traditional concept that SLE is mainly caused by adaptive immune abnormalities, and confirms that innate immune cell abnormalities play a key role in systemic autoimmunity
.
Therefore, it will inevitably stimulate discussion in the academic community about the interaction between the innate and adaptive immune systems in maintaining immune homeostasis, and how specific perturbations of this interaction can lead to autoimmunity
.
At the same time, this study also opened up a new target direction for the treatment of SLE
.
Serum factors reduce SLE neutrophil activity.
SLE patients showed a significantly lower neutrophil count than healthy people and other immune diseases, and the cell viability rate was also significantly reduced.
The above phenomenon was significantly alleviated after treatment
.
The research team speculates that this phenomenon is related to serum, and tested the serum inflammatory factor profile of SLE patients, and found that the specifically elevated type I interferon in SLE can significantly induce neutrophil death, and blocking type I interferon can alleviate the SLE serum Induced cell death
.
The production of autoantibodies is an important feature of lupus.
The research team also found that the proportion of dsDNA antibodies in the IgG of lupus patients was significantly negatively correlated with the neutrophil count, and the isolated SLE IgG significantly promoted the death of neutrophils.
The ability of SLE serum containing IgG to induce the death of neutrophils is reduced
.
SLE neutrophils show the characteristics of iron death.
In order to study the specific forms of death of neutrophils, the research team observed the morphology of SLE neutrophils through electron microscopy and found that their mitochondria showed the characteristics of iron death.
Further verification also showed that SLE The content of lipid-ROS (lipid-ROS) in neutrophils was significantly higher than that of healthy controls.
Anti-iron death drugs can block the effect of SLE serum on neutrophil death
.
At the same time, type I interferon and SLE IgG can significantly induce iron death of neutrophils
.
It is worth noting that the research team found that the process of neutrophil extracellular capture network (NETosis) is not the main death form of lupus neutrophils
.
Inhibition of iron death can slow down the progress of lupus mice.
The administration of iron death inhibitor Liproxstatin-1 can significantly alleviate the progress of lupus in MRL.
lpr mice.
Specific indicators include proteinuria, anti-dsDNA, reduction of inflammatory factor levels, spleen, and lymph nodes.
Shrinkage and restoration of complement C3
.
Autoantibodies and interferon reduce the expression of neutrophil GPX4.
The research team used neutrophil transcriptome sequencing and found that 23 iron death-related genes were abnormally expressed in patients with lupus, among which glutathione peroxidase 4 ( GPX4) was significantly reduced, and the degree of reduction was related to the activity of lupus disease, and recovered after treatment
.
The research team found that SLE serum can reduce the expression of GPX4, and blocking type I interferon or SLE IgG can alleviate the reduction of GPX4, and this phenomenon shows neutrophil specificity
.
Mice with specific neutrophil GPX4 haploid deficiency spontaneously developed lupus phenotypes.
Next, the research team constructed a mouse model of neutrophil GPX4 knockdown and found that the model spontaneously developed lupus phenotypes, including skin lesions.
, Kidney immune complex deposition, anti-dsDNA and inflammatory factors increased, the mouse showed obvious spleen and lymph node enlargement at the age of 12 months, which better mimics the human lupus phenotype
.
CaMKIV-CREM-GPX4 pathway In order to study the specific mechanism of the decrease of neutrophil GPX4 and iron death in patients with lupus, the researchers used chromatin immunoprecipitation and DNA-pulldown methods to find the promoter of patient neutrophil GPX4 The abnormal binding of CREM-suppressed transcription factors, SLE serum, or type I interferon and SLE IgG can activate the CaMKIV molecule so that CREM binds to the promoter region of GPX4 and inhibits the transcription of GPX4
.
In Crem-/- and Camk4-/- lupus animal models, the decline of GPX4 was also significantly alleviated
.
In summary, the main new findings of the study are: 1.
There is obvious spontaneous iron death in neutrophils of patients with active SLE, and after effective treatment, cellular iron death returns to normal levels
.
2.
Serum autoreactive IgG and type I interferon can induce iron death of neutrophils
.
3.
Iron death inhibitors can significantly reduce the disease progression of lupus mice
.
4.
Mouse myeloid-specific haploid knockout of iron death negative regulatory protein GPX4 can induce a typical lupus-like phenotype
.
5.
Serum autoreactive IgG and type I interferon inhibit the expression of GPX4 in neutrophils of SLE patients through the CaMKIV/CREM pathway, leading to the accumulation of lipid reactive oxygen species in the cells and the iron death of neutrophils
.
Professor Zhang Xuan pointed out: “Past research mainly emphasized the role of adaptive immunity in inducing systemic autoimmune diseases.
Our research has subverted the traditional concept to some extent.
The abnormality of cells of the innate immune system can lead to the system the occurrence of autoimmunity
.
specifically, namely neutrophils GPX4 deficiency leads to typical SLE phenotype iron can occur after death
.
effect of previous iron death in autoimmune diseases not reported, our research shows that it is not only lupus An important reason for the reduction of white blood cells in patients, and it can induce a cascade of pathological reactions to promote the development of SLE
.
" Original link: https://doi.
org/10.
1038/s41590-021-00993-3 Non-original articles] The copyright of this article belongs to 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
.
