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The aging of the population is a major social problem facing our country and the world at present.
With the increase of age, the normal body will show an aging state, and the aging of the immune system is one of the prominent and important problems, and it is also prone to chronic chronic diseases in elderly individuals.
An important cause of inflammation and autoimmune diseases.
T cell-mediated adaptive immunity is the key driving force for the body to induce autoimmune inflammation.
Although thymus atrophy caused by aging will reduce the initial T cell output, the number of peripheral T cells in the elderly does not decrease.
The reason is Because peripheral T cells undergo homeostatic proliferation and activation under the aging state, which promotes the occurrence and development of inflammation, however, aging induces the steady-state proliferation of T cells and promotes the specific regulation mechanism of autoimmune inflammation.
still not clear.
Aging will promote the increase of free DNA in cells and in the circulatory system, and the reaction to its own DNA will increase the body’s risk of inducing autoimmune diseases.
If the genes of enzymes (such as Trex1, Dnase I or DNase II) that degrade DNA in the cytoplasm Deletion will induce spontaneous systemic autoimmune inflammation in mice.
Similarly, loss-of-function mutations in human DNASE1 or TREX1 are also related to some people's autoimmune diseases.
Therefore, the accumulation of DNA induced by senescence may be the key to the development of its own immunity.
In addition, studies have shown that removal of T cells can significantly inhibit the spontaneous autoimmune inflammation and death of Trex1 knockout mice, suggesting that T cells may have a potential role in regulating DNA-induced autoimmunity.
On March 4, 2021, Xiao Yichuan's research group from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences and Zheng Mingyue, a researcher from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published a research paper Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell in the journal Immunity potentiates T cell activation and aging-related autoimmune inflammation.
This study reveals that KU complex mediates DNA perception in CD4+ T cells, which in turn mediates the regulatory mechanism of aging-related autoimmune diseases.
In this study, the researchers found that there is a large accumulation of DNA in the cytoplasm of CD4+ T cells in old mice and humans, and this accumulated DNA will promote the proliferation and activation of CD4+ T cells induced by TCR, and promote the mouse The occurrence and development of autoimmune inflammation indicates that T cells themselves can promote their functional activation through DNA sensing.
The perception of DNA in innate immune cells mainly depends on the cGAS/STING system, which then mediates the production of sex I interferon by activating IRF3.
Further studies have found that the expression level of cGAS in CD4+ T cells is very low, so the increase in DNA will not promote the activation of IRF3 downstream of cGAS/STING and the production of interferon I.
The researchers then used mass spectrometry combined with western blotting to find that the cytoplasmic DNA in T cells does not bind to cGAS, but to the KU complex (KU70/KU80).
If the small molecule inhibitor STL127705 is used to block the binding of KU complex to DNA, it will significantly inhibit the proliferation and activation of DNA-induced CD4+ T cells, thereby alleviating the occurrence and development of autoimmune inflammation in old mice, indicating that DNA-induced T cell function activation is indeed mediated by DNA sensing through the KU complex.
Normally, the KU complex and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) mediate the repair of DNA damage in the nucleus.
However, this study found that the KU complex is expressed in a large amount in the cytoplasm of T cells.
It senses the DNA accumulated in the CD4+ T cytoplasm and promotes the phosphorylation activation of DNA-PKcs, which in turn mediates the phosphorylation of ZAK at the T169 site.
Then phosphorylate AKT to activate the downstream mTOR pathway, thereby enhancing the proliferation and activation of CD4+ T cells.
Therefore, the activation of the DNA sensing pathway mediated by the KU complex in CD4+ T cells is a key mechanism leading to the occurrence and development of autoimmune inflammation in aged mice.
In order to explore therapeutic strategies to interfere with this newly discovered DNA sensing pathway to suppress aging-related autoimmune inflammation, the researchers used calorie restriction (CR) or simulated intermittent feeding (FMD) to treat elderly mice and found these two dieting patterns Can significantly reduce the DNA damage and cytoplasmic DNA accumulation of CD4+ T cells in old mice, thereby inhibiting the phosphorylation of ZAK-T169 and the activation of downstream AKT/mTOR signals, and finally inhibiting the activation of CD4+ T cells and aging-related Symptoms of autoimmune disease.
Furthermore, based on the key protein kinase ZAK identified in the DNA sensing pathway, the researchers used deep learning combined with molecular simulation to screen from approximately 130,000 compound libraries to obtain a small molecule compound iZAK2 that can specifically inhibit the activity of ZAK kinase.
It is found that iZAK2 can effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune diseases in elderly mice.
In summary, this study revealed that cGAS/STING-independent DNA sensing signaling pathways in senescent CD4+ T cells can promote the activation and proliferation of T cells and lead to the occurrence and development of aging-related autoimmune diseases.
Further research and development of inhibitors that block DNA sensing signal transduction in T cells may be beneficial to clinical treatment of aging-related autoimmune diseases.
The cartoon and mechanism diagram of DNA perception in aging CD4+ T cells to promote their activation and autoimmune inflammation.
Wang Yan, PhD student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and researcher Xiao Yichuan and researcher Zheng Mingyue are the paper Co-corresponding author.Xiao Yichuan's research group at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences mainly focuses on the immune regulation of aging and related pathogenic mechanisms.
In the past 5 years, it has been in Immunity (2021), JEM (2018, 2020, 2021), Nature Communications (2018, 2019) ), PLOS Biology (2020), Cellular & Molecular Immunology (2021) and other journals published corresponding author articles.
Xiao Yichuan’s research team is now recruiting postdoctoral fellows.
Interested parties are welcome to contact us.
The recruitment majors include but are not limited to immunology, tumor biology, neurobiology or computational biology, etc.
Resume delivery (candidates please send relevant materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to submit the original resume link: https://doi.
org/10.
1016/j.
immuni.
2021.
02.
003 Platemaker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
With the increase of age, the normal body will show an aging state, and the aging of the immune system is one of the prominent and important problems, and it is also prone to chronic chronic diseases in elderly individuals.
An important cause of inflammation and autoimmune diseases.
T cell-mediated adaptive immunity is the key driving force for the body to induce autoimmune inflammation.
Although thymus atrophy caused by aging will reduce the initial T cell output, the number of peripheral T cells in the elderly does not decrease.
The reason is Because peripheral T cells undergo homeostatic proliferation and activation under the aging state, which promotes the occurrence and development of inflammation, however, aging induces the steady-state proliferation of T cells and promotes the specific regulation mechanism of autoimmune inflammation.
still not clear.
Aging will promote the increase of free DNA in cells and in the circulatory system, and the reaction to its own DNA will increase the body’s risk of inducing autoimmune diseases.
If the genes of enzymes (such as Trex1, Dnase I or DNase II) that degrade DNA in the cytoplasm Deletion will induce spontaneous systemic autoimmune inflammation in mice.
Similarly, loss-of-function mutations in human DNASE1 or TREX1 are also related to some people's autoimmune diseases.
Therefore, the accumulation of DNA induced by senescence may be the key to the development of its own immunity.
In addition, studies have shown that removal of T cells can significantly inhibit the spontaneous autoimmune inflammation and death of Trex1 knockout mice, suggesting that T cells may have a potential role in regulating DNA-induced autoimmunity.
On March 4, 2021, Xiao Yichuan's research group from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences and Zheng Mingyue, a researcher from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published a research paper Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell in the journal Immunity potentiates T cell activation and aging-related autoimmune inflammation.
This study reveals that KU complex mediates DNA perception in CD4+ T cells, which in turn mediates the regulatory mechanism of aging-related autoimmune diseases.
In this study, the researchers found that there is a large accumulation of DNA in the cytoplasm of CD4+ T cells in old mice and humans, and this accumulated DNA will promote the proliferation and activation of CD4+ T cells induced by TCR, and promote the mouse The occurrence and development of autoimmune inflammation indicates that T cells themselves can promote their functional activation through DNA sensing.
The perception of DNA in innate immune cells mainly depends on the cGAS/STING system, which then mediates the production of sex I interferon by activating IRF3.
Further studies have found that the expression level of cGAS in CD4+ T cells is very low, so the increase in DNA will not promote the activation of IRF3 downstream of cGAS/STING and the production of interferon I.
The researchers then used mass spectrometry combined with western blotting to find that the cytoplasmic DNA in T cells does not bind to cGAS, but to the KU complex (KU70/KU80).
If the small molecule inhibitor STL127705 is used to block the binding of KU complex to DNA, it will significantly inhibit the proliferation and activation of DNA-induced CD4+ T cells, thereby alleviating the occurrence and development of autoimmune inflammation in old mice, indicating that DNA-induced T cell function activation is indeed mediated by DNA sensing through the KU complex.
Normally, the KU complex and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) mediate the repair of DNA damage in the nucleus.
However, this study found that the KU complex is expressed in a large amount in the cytoplasm of T cells.
It senses the DNA accumulated in the CD4+ T cytoplasm and promotes the phosphorylation activation of DNA-PKcs, which in turn mediates the phosphorylation of ZAK at the T169 site.
Then phosphorylate AKT to activate the downstream mTOR pathway, thereby enhancing the proliferation and activation of CD4+ T cells.
Therefore, the activation of the DNA sensing pathway mediated by the KU complex in CD4+ T cells is a key mechanism leading to the occurrence and development of autoimmune inflammation in aged mice.
In order to explore therapeutic strategies to interfere with this newly discovered DNA sensing pathway to suppress aging-related autoimmune inflammation, the researchers used calorie restriction (CR) or simulated intermittent feeding (FMD) to treat elderly mice and found these two dieting patterns Can significantly reduce the DNA damage and cytoplasmic DNA accumulation of CD4+ T cells in old mice, thereby inhibiting the phosphorylation of ZAK-T169 and the activation of downstream AKT/mTOR signals, and finally inhibiting the activation of CD4+ T cells and aging-related Symptoms of autoimmune disease.
Furthermore, based on the key protein kinase ZAK identified in the DNA sensing pathway, the researchers used deep learning combined with molecular simulation to screen from approximately 130,000 compound libraries to obtain a small molecule compound iZAK2 that can specifically inhibit the activity of ZAK kinase.
It is found that iZAK2 can effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune diseases in elderly mice.
In summary, this study revealed that cGAS/STING-independent DNA sensing signaling pathways in senescent CD4+ T cells can promote the activation and proliferation of T cells and lead to the occurrence and development of aging-related autoimmune diseases.
Further research and development of inhibitors that block DNA sensing signal transduction in T cells may be beneficial to clinical treatment of aging-related autoimmune diseases.
The cartoon and mechanism diagram of DNA perception in aging CD4+ T cells to promote their activation and autoimmune inflammation.
Wang Yan, PhD student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and researcher Xiao Yichuan and researcher Zheng Mingyue are the paper Co-corresponding author.Xiao Yichuan's research group at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences mainly focuses on the immune regulation of aging and related pathogenic mechanisms.
In the past 5 years, it has been in Immunity (2021), JEM (2018, 2020, 2021), Nature Communications (2018, 2019) ), PLOS Biology (2020), Cellular & Molecular Immunology (2021) and other journals published corresponding author articles.
Xiao Yichuan’s research team is now recruiting postdoctoral fellows.
Interested parties are welcome to contact us.
The recruitment majors include but are not limited to immunology, tumor biology, neurobiology or computational biology, etc.
Resume delivery (candidates please send relevant materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to submit the original resume link: https://doi.
org/10.
1016/j.
immuni.
2021.
02.
003 Platemaker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
