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The interleukin-17 (IL-17) cytokine family consists of six members (IL-17A to IL-17F).
Among them, IL-17A and IL-17F are mainly secreted by Th17 cells, with IL-17RA/IL-17RC or IL-17RA/IL-17RD heterodimer as the receptor, participating in immunity against bacterial and fungal infections and various The development of autoimmune diseases.
IL-17C and IL-17E are secreted by epithelial cells and regulate tissue inflammation in an autocrine manner.
They can also mediate the differentiation and function of certain helper T cell subsets (such as Th2, Th17).
IL-17D is the least studied member of this family.
Its gene was discovered in 2002, but the receptor is still unknown.
In addition, there is a lack of in-depth research on the biological function and mechanism of IL-17D.
On April 13, 2021, the team of Academician Dong Chen from the Institute of Immunology of Tsinghua University published a research paper titled: Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93 in the top immunology journal Immunity.
This study identified the functional receptor of IL-17D as CD93 for the first time, and revealed that IL-17D regulates the function of ILC3 cells by binding to CD93 and participates in maintaining intestinal homeostasis.
In this study, the researchers found in the DSS-induced mouse colitis model that compared with wild-type mice, IL-17D gene-deficient mouse colitis was significantly worsened by weight loss, colon shortening, and epithelial cells.
The injury worsened and the expression of inflammation-related cytokines increased significantly.In addition to the DSS-induced colitis model, the researchers found that IL-17D deletion also caused mice to be susceptible to AOM-DSS-induced colon cancer and C.
rodentium infection.
These phenotypes indicate that IL-17D plays a protective role in intestinal diseases.
In addition, the researchers found that the protective effect is mainly achieved through the participation of IL-17D secreted by epithelial cells.
In terms of mechanism, researchers found that IL-17D mainly acts through natural lymphocyte ILC3.
Regardless of whether it is in a steady state or an inflammatory environment, in IL-17D-deficient mice, the ability of ILC3 to secrete IL-22 and the expression of IL-22-dependent downstream antibacterial proteins (RegIIIβ, RegIIIγ) are inhibited, which in turn causes The intestinal flora of IL-17D-deficient mice is dysregulated.
Further research found that in IL-17D-deficient mice, supplementation of IL-22 protein slowed the progression of colitis disease; supplementation of IL-17D protein on the one hand can reduce the incidence of colitis, on the other hand can restore Il22, Reg3b, Reg3g The level of expression.
These findings indicate that IL-17D exerts its biological effects by regulating the function of ILC3 cells.
The research team then identified the receptor for IL-17D for the first time.
To this end, the researchers first used the 293T overexpression system to screen the potential receptors of IL-17D from the IL-17 receptor family (IL-17RA to IL-17RE), and found that IL-17D is not related to IL-17D in the family.
Any combination of members, including homodimer or heterodimer form.
Through binding experiments with various cell lines, it was found that IL-17D can bind to RAW264.
7 cells, suggesting that IL-17D receptors may exist on the cells.
After excluding the possibility of binding to the classic IL-17 receptor, the researchers used immunoprecipitation-mass spectrometry (IP-MS) technology to identify the IL-17D receptor using RAW264.
7 as a tool cell. From the more than 200 proteins in the mass spectrometry results, the researchers performed 293T overexpression and IL-17D protein binding experiments on 21 membrane proteins, and found that only 293T cells overexpressing CD93 can bind to IL-17D; In addition, surface plasmon resonance experiments confirmed that CD93 is the receptor of IL-17D, and its affinity is close to the binding of IL-17F and IL-17RA of the same family.
In addition, through staining and single-cell RNA-seq analysis in the database, the researchers found that CD93 is mainly expressed in ILC3 cells, especially effector ILC3 cells.
Transcriptomics data show that compared with CD93-negative ILC3 cells, CD93-positive ILC3 cells highly express ILC3 effector molecules, such as Il23r, Il1r, Rorc, Rora, Id2, Il22, Il17a, Csf2, etc.
that participate in cell-cytokine receptor interactions And the genes for the defense response.
Using CRISPR-Cas9 technology to construct Cd93 knockout mice, the researchers found that the binding of IL-17D to intestinal ILC3 cells depends on the expression of CD93, and the lack of CD93 also makes the mice sensitive to the induction of colitis and colon cancer.
In order to further explore the regulatory effects of IL-17D-CD93 signaling on ILC3 cells, the researchers also constructed ILC3 cell-specific CD93 knockout mice (RorccreCD93fl/fl).
Consistent with the phenotype of IL-17D deficiency, the ability of ILC3 cells in RorccreCD93fl/fl mice to secrete IL-22 was severely affected, and the absence of CD93 on ILC3 cells exacerbated the symptoms of colitis in mice.
This study reveals that CD93 is the receptor of IL-17D from the biochemical level, cellular level and physiological function.
At the same time, it is of great significance for understanding the role and mechanism of IL-17D in the immune system and related diseases.
This work is another milestone result of the long-term and systematic study of IL-17 and its receptor family by the team of Academician Dong Chen.
It is of great significance for understanding this cytokine family and mucosal immunity, and it also suggests a new target for the treatment of inflammatory diseases.
point. Jin Ling, a postdoctoral fellow at Tsinghua University School of Medicine, is the first author of the paper.
Academician Dong Chen, a professor at the Institute of Immunology of Tsinghua University and a researcher at Renji Hospital, Shanghai Jiaotong University School of Medicine, is the corresponding author of this article.
This research is supported by the key R&D projects of the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Beijing Municipal Science and Technology Commission.
Original link: Open for reprinting This article is open for reprinting: Just leave a message in this article and let us know
Among them, IL-17A and IL-17F are mainly secreted by Th17 cells, with IL-17RA/IL-17RC or IL-17RA/IL-17RD heterodimer as the receptor, participating in immunity against bacterial and fungal infections and various The development of autoimmune diseases.
IL-17C and IL-17E are secreted by epithelial cells and regulate tissue inflammation in an autocrine manner.
They can also mediate the differentiation and function of certain helper T cell subsets (such as Th2, Th17).
IL-17D is the least studied member of this family.
Its gene was discovered in 2002, but the receptor is still unknown.
In addition, there is a lack of in-depth research on the biological function and mechanism of IL-17D.
On April 13, 2021, the team of Academician Dong Chen from the Institute of Immunology of Tsinghua University published a research paper titled: Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93 in the top immunology journal Immunity.
This study identified the functional receptor of IL-17D as CD93 for the first time, and revealed that IL-17D regulates the function of ILC3 cells by binding to CD93 and participates in maintaining intestinal homeostasis.
In this study, the researchers found in the DSS-induced mouse colitis model that compared with wild-type mice, IL-17D gene-deficient mouse colitis was significantly worsened by weight loss, colon shortening, and epithelial cells.
The injury worsened and the expression of inflammation-related cytokines increased significantly.In addition to the DSS-induced colitis model, the researchers found that IL-17D deletion also caused mice to be susceptible to AOM-DSS-induced colon cancer and C.
rodentium infection.
These phenotypes indicate that IL-17D plays a protective role in intestinal diseases.
In addition, the researchers found that the protective effect is mainly achieved through the participation of IL-17D secreted by epithelial cells.
In terms of mechanism, researchers found that IL-17D mainly acts through natural lymphocyte ILC3.
Regardless of whether it is in a steady state or an inflammatory environment, in IL-17D-deficient mice, the ability of ILC3 to secrete IL-22 and the expression of IL-22-dependent downstream antibacterial proteins (RegIIIβ, RegIIIγ) are inhibited, which in turn causes The intestinal flora of IL-17D-deficient mice is dysregulated.
Further research found that in IL-17D-deficient mice, supplementation of IL-22 protein slowed the progression of colitis disease; supplementation of IL-17D protein on the one hand can reduce the incidence of colitis, on the other hand can restore Il22, Reg3b, Reg3g The level of expression.
These findings indicate that IL-17D exerts its biological effects by regulating the function of ILC3 cells.
The research team then identified the receptor for IL-17D for the first time.
To this end, the researchers first used the 293T overexpression system to screen the potential receptors of IL-17D from the IL-17 receptor family (IL-17RA to IL-17RE), and found that IL-17D is not related to IL-17D in the family.
Any combination of members, including homodimer or heterodimer form.
Through binding experiments with various cell lines, it was found that IL-17D can bind to RAW264.
7 cells, suggesting that IL-17D receptors may exist on the cells.
After excluding the possibility of binding to the classic IL-17 receptor, the researchers used immunoprecipitation-mass spectrometry (IP-MS) technology to identify the IL-17D receptor using RAW264.
7 as a tool cell. From the more than 200 proteins in the mass spectrometry results, the researchers performed 293T overexpression and IL-17D protein binding experiments on 21 membrane proteins, and found that only 293T cells overexpressing CD93 can bind to IL-17D; In addition, surface plasmon resonance experiments confirmed that CD93 is the receptor of IL-17D, and its affinity is close to the binding of IL-17F and IL-17RA of the same family.
In addition, through staining and single-cell RNA-seq analysis in the database, the researchers found that CD93 is mainly expressed in ILC3 cells, especially effector ILC3 cells.
Transcriptomics data show that compared with CD93-negative ILC3 cells, CD93-positive ILC3 cells highly express ILC3 effector molecules, such as Il23r, Il1r, Rorc, Rora, Id2, Il22, Il17a, Csf2, etc.
that participate in cell-cytokine receptor interactions And the genes for the defense response.
Using CRISPR-Cas9 technology to construct Cd93 knockout mice, the researchers found that the binding of IL-17D to intestinal ILC3 cells depends on the expression of CD93, and the lack of CD93 also makes the mice sensitive to the induction of colitis and colon cancer.
In order to further explore the regulatory effects of IL-17D-CD93 signaling on ILC3 cells, the researchers also constructed ILC3 cell-specific CD93 knockout mice (RorccreCD93fl/fl).
Consistent with the phenotype of IL-17D deficiency, the ability of ILC3 cells in RorccreCD93fl/fl mice to secrete IL-22 was severely affected, and the absence of CD93 on ILC3 cells exacerbated the symptoms of colitis in mice.
This study reveals that CD93 is the receptor of IL-17D from the biochemical level, cellular level and physiological function.
At the same time, it is of great significance for understanding the role and mechanism of IL-17D in the immune system and related diseases.
This work is another milestone result of the long-term and systematic study of IL-17 and its receptor family by the team of Academician Dong Chen.
It is of great significance for understanding this cytokine family and mucosal immunity, and it also suggests a new target for the treatment of inflammatory diseases.
point. Jin Ling, a postdoctoral fellow at Tsinghua University School of Medicine, is the first author of the paper.
Academician Dong Chen, a professor at the Institute of Immunology of Tsinghua University and a researcher at Renji Hospital, Shanghai Jiaotong University School of Medicine, is the corresponding author of this article.
This research is supported by the key R&D projects of the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Beijing Municipal Science and Technology Commission.
Original link: Open for reprinting This article is open for reprinting: Just leave a message in this article and let us know
