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Written by Xueyue | xi Myelodysplastic syndromes (myelodysplastic syndromes, MDSs) patients have severe anemia, and the blood cells in the bone marrow are immature.
The mechanism has not yet been elucidated.
Some patients with MDSs have RIOK2 gene deletion (Right open-reading-frame kinase 2, RIOK2).
Especially in MDS patients with missing RIOK2, the performance of anemia is particularly obvious.
RIOK2 encodes an atypical serine-threonine protein kinase, which is an essential subunit of the ribosome before 40s.
The patient’s anemia is related to the lack of a single dose, and insufficient synthesis of ribosomal proteins such as RPS14 and RPS19.
It has been reported that innate immune activation, inflammation and abnormal immune function are the pathogenesis of MDSs.
There are abnormal expressions of many cytokines in MDS.
In patients with chronic inflammation, cytokines in the bone marrow microenvironment are related to the inhibition of erythropoiesis.
However, the relationship between the immune system and ribosomal protein haploinsufficiency and the pathogenesis of MDS is still unclear.
On March 21, 2021, Laurie H.
Glimcher's team from Harvard University published an article titled Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias in Nature Immonology.
The study found that in stress-induced and MDSs anemia, IL22 can promote the apoptosis of erythroid progenitor cells, leading to anemia; blocking the IL22 pathway can reverse anemia.
The author first used the hematopoietic cell-specific single knockout RIOK2 mouse Riok2f/+Vav1-cre to verify the previous findings (double knockout mice are embryonic death).
By comparison, it was found that the nascent protein in bone marrow cells of single knockout mice was significantly reduced.
Next, the authors tried to confirm whether the anemia caused by a single dose of RIOK2 was secondary to the differentiation defect of bone marrow-derived erythroid cells.
The author used Ter119 and CD71 two markers to detect the differentiation of red blood cells at different stages.
The authors found that erythrocyte production in the bone marrow of single knockout mice was impaired, and the apoptosis of erythrocyte precursor cells increased.
The author also verified the differentiation defect of bone marrow erythroid cells in single knockout mice using the acute hemolytic stress model.
The authors also found that knockout mice increased bone marrow production.
Although the number of red blood cells in the peripheral blood decreased, the number of monocytes increased and the number of neutrophils decreased.
In summary, it was found that insufficient haplodose of RIKO2 can cause abnormal bone marrow proliferation and affect the differentiation of early hematopoietic progenitor cells.
Quantitative analysis of proteomics found that RIOK2 single knocking would increase the expression of alarm proteins (S100A8, S100A9, CAMP, NGP) in red blood cell precursor cells.
Using MetaCore pathway to analyze proteomics, it was found that the immune response in single knockout mice was significantly increased.
Therefore, the authors tested whether the functions of various immune cells were abnormal and found that the differentiation of Th22 that secretes IL22 was significantly increased.
In order to explore the mechanism of the rise of Th22, the author conducted a transcriptome analysis of Th22 and identified that the p53 pathway was significantly activated and p53 expression increased.
P53 is activated by decreased expression of ribosomal protein.
To test whether p53 drives IL22 transcription.
Chromatin immunoprecipitation found that p53 can bind to the IL22 promoter.
If p53 is deleted, IL22 expression can be suppressed.
These data indicate that under-dose of RIOK2 can activate p53 and drive IL-22 expression to increase.
Knockout of IL-22 showed an increase in the number of peripheral red blood cells in RIOK2 knockout mice.
Using IL22 neutralizing antibody to act on knockout mice and stress anemia mouse models found that IL22 neutralization can inhibit the apoptosis of erythroid progenitor cells.
These data indicate that targeting IL22 can reduce the degree of anemia in knockout mice and the disease in stress anemia models.
The use of exogenous IL22 in mice can induce apoptosis of erythroid progenitor cells.
Detection of the expression and distribution of IL22 receptor IL22RA1 found that IL22RA1 was particularly high in erythroid progenitor cells.
After knocking out the IL22 receptor, the symptoms of anemia in the knockout mice were alleviated.
The detection of MDS patients with RIOK2 haploid deletion found that the data obtained in the mouse model can be verified.
In patients with chronic kidney disease and anemia, IL22 was significantly higher than that in patients without anemia.
10% to 20% of these patients are resistant to erythropoiesis agents, indicating other pathogenic mechanisms.
This study suggests that IL22 is related to anemia caused by chronic kidney disease.
This study shows that IL22 can directly regulate the differentiation of erythroid cells in the bone marrow, and IL22 can act on erythroid precursor cells through IL22 receptors to cause their apoptosis.
This article provides a new approach for the treatment of MDS, stress anemia and chronic disease-induced anemia.
Targeting IL22 is expected to become a new method for the treatment of patients who are resistant to erythrocyte therapy.
Original link: https://doi.
org/10.
1038/s41590-021-00895-4 Platemaker: Notes for reprinting on the 11th [Original article] Original article of BioArt, welcome to forward and share by individuals, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
The mechanism has not yet been elucidated.
Some patients with MDSs have RIOK2 gene deletion (Right open-reading-frame kinase 2, RIOK2).
Especially in MDS patients with missing RIOK2, the performance of anemia is particularly obvious.
RIOK2 encodes an atypical serine-threonine protein kinase, which is an essential subunit of the ribosome before 40s.
The patient’s anemia is related to the lack of a single dose, and insufficient synthesis of ribosomal proteins such as RPS14 and RPS19.
It has been reported that innate immune activation, inflammation and abnormal immune function are the pathogenesis of MDSs.
There are abnormal expressions of many cytokines in MDS.
In patients with chronic inflammation, cytokines in the bone marrow microenvironment are related to the inhibition of erythropoiesis.
However, the relationship between the immune system and ribosomal protein haploinsufficiency and the pathogenesis of MDS is still unclear.
On March 21, 2021, Laurie H.
Glimcher's team from Harvard University published an article titled Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias in Nature Immonology.
The study found that in stress-induced and MDSs anemia, IL22 can promote the apoptosis of erythroid progenitor cells, leading to anemia; blocking the IL22 pathway can reverse anemia.
The author first used the hematopoietic cell-specific single knockout RIOK2 mouse Riok2f/+Vav1-cre to verify the previous findings (double knockout mice are embryonic death).
By comparison, it was found that the nascent protein in bone marrow cells of single knockout mice was significantly reduced.
Next, the authors tried to confirm whether the anemia caused by a single dose of RIOK2 was secondary to the differentiation defect of bone marrow-derived erythroid cells.
The author used Ter119 and CD71 two markers to detect the differentiation of red blood cells at different stages.
The authors found that erythrocyte production in the bone marrow of single knockout mice was impaired, and the apoptosis of erythrocyte precursor cells increased.
The author also verified the differentiation defect of bone marrow erythroid cells in single knockout mice using the acute hemolytic stress model.
The authors also found that knockout mice increased bone marrow production.
Although the number of red blood cells in the peripheral blood decreased, the number of monocytes increased and the number of neutrophils decreased.
In summary, it was found that insufficient haplodose of RIKO2 can cause abnormal bone marrow proliferation and affect the differentiation of early hematopoietic progenitor cells.
Quantitative analysis of proteomics found that RIOK2 single knocking would increase the expression of alarm proteins (S100A8, S100A9, CAMP, NGP) in red blood cell precursor cells.
Using MetaCore pathway to analyze proteomics, it was found that the immune response in single knockout mice was significantly increased.
Therefore, the authors tested whether the functions of various immune cells were abnormal and found that the differentiation of Th22 that secretes IL22 was significantly increased.
In order to explore the mechanism of the rise of Th22, the author conducted a transcriptome analysis of Th22 and identified that the p53 pathway was significantly activated and p53 expression increased.
P53 is activated by decreased expression of ribosomal protein.
To test whether p53 drives IL22 transcription.
Chromatin immunoprecipitation found that p53 can bind to the IL22 promoter.
If p53 is deleted, IL22 expression can be suppressed.
These data indicate that under-dose of RIOK2 can activate p53 and drive IL-22 expression to increase.
Knockout of IL-22 showed an increase in the number of peripheral red blood cells in RIOK2 knockout mice.
Using IL22 neutralizing antibody to act on knockout mice and stress anemia mouse models found that IL22 neutralization can inhibit the apoptosis of erythroid progenitor cells.
These data indicate that targeting IL22 can reduce the degree of anemia in knockout mice and the disease in stress anemia models.
The use of exogenous IL22 in mice can induce apoptosis of erythroid progenitor cells.
Detection of the expression and distribution of IL22 receptor IL22RA1 found that IL22RA1 was particularly high in erythroid progenitor cells.
After knocking out the IL22 receptor, the symptoms of anemia in the knockout mice were alleviated.
The detection of MDS patients with RIOK2 haploid deletion found that the data obtained in the mouse model can be verified.
In patients with chronic kidney disease and anemia, IL22 was significantly higher than that in patients without anemia.
10% to 20% of these patients are resistant to erythropoiesis agents, indicating other pathogenic mechanisms.
This study suggests that IL22 is related to anemia caused by chronic kidney disease.
This study shows that IL22 can directly regulate the differentiation of erythroid cells in the bone marrow, and IL22 can act on erythroid precursor cells through IL22 receptors to cause their apoptosis.
This article provides a new approach for the treatment of MDS, stress anemia and chronic disease-induced anemia.
Targeting IL22 is expected to become a new method for the treatment of patients who are resistant to erythrocyte therapy.
Original link: https://doi.
org/10.
1038/s41590-021-00895-4 Platemaker: Notes for reprinting on the 11th [Original article] Original article of BioArt, welcome to forward and share by individuals, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
