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Written | Edited by Hu Xiaohua | Qi Crohn's disease (CD) is a chronic inflammatory bowel disease, and its pathogenic mechanism has not yet been clearly studied.
Among them, NOD2 loss-of-function mutations are considered to be an important risk factor for the occurrence of CD [1].
Although scientists have now realized that the imbalance of macrophage-fibroblast system homeostasis in the microenvironment caused by NOD2 loss-of-function mutations may be an important driving factor leading to the occurrence of CD [2], the specific pathogenicity of NOD2 loss Mechanism has always been an unresolved issue in this area.
Recently, Professor Judy H.
Cho’s research team from the Department of Genetics and Genomics of Icahn Medical College of Mount Sinai published a research article titled A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn's disease in the journal Nature, revealing The specific mechanism of the occurrence of Crohn’s disease caused by the loss of NOD2 function was found, and a new therapeutic target for Crohn’s disease was found.
First, the author identified a type of CD14+PDGFRA+ fibroblasts.
By comparing inflamed and non-inflamed ileum tissues, the authors found that CD14+PDGFRA+ cells in inflamed ileum tissues are rich in pro-fibrotic factors (such as WT1 and IL11).
Set.
NOD2 can sense the components of bacteria when infection occurs and is expressed in fibroblasts activated by inflammation.
Therefore, the authors speculate that the loss of NOD2 function may drive the abnormal differentiation of CD14+ peripheral blood mononuclear cells (PDMBs) to form fibrotic macrophages.
To verify this conjecture, the authors first analyzed PDMBs of normal (NOD2WT) and NOD2 mutations (NOD2MT) volunteers.
They found that as the copy number of NOD2 risk alleles increased, the expression levels of fibroblast genes in these cells also increased.
Increased accordingly.
Further, by verifying in wild-type (nod2wt), nod2 mutant (nod2sa21011) and nod2 knockout (nod2mss13) zebrafish, the authors once again proved that loss of NOD2 function does indeed increase pro-fibrosis-related transcription factors in an inflammatory state.
expression.
These experimental results indicate that the loss of NOD2 will reshape the fate of macrophages in an inflammatory state, making them a fibrotic phenotype.
In addition, the authors found that loss of NOD2 can aggravate the CD phenotype and lead to excessive activation of the transcription level of fibroblasts and pro-inflammatory macrophages.
So how does the loss of NOD2 affect the transcription levels of fibroblasts and pro-inflammatory macrophages? By analyzing the scRNAseq data of fibroblasts and macrophages from normal and NOD2 mutant volunteers, the authors found that in NOD2 mutant volunteers, STAT3 is enriched in both types of cells, and STAT3 increases pro-inflammatory /Transcription of pro-fibrotic factors, suggesting that STAT3 may play an important regulatory role in this process.
Therefore, the authors speculate that blocking the common cytokine receptor subunit gp130 upstream of STAT3 with the small molecule inhibitor bazedoxifene may inhibit the excessive activation of fibroblasts and pro-inflammatory macrophages in an inflammatory state.
Experimental results show that bazedoxifene can indeed inhibit the excessive activation of fibroblasts and pro-inflammatory macrophages, thereby reducing the DSS-induced enteritis phenotype.
In general, the research team used people with NOD2 mutations and zebrafish lacking nod2 as the research object, and using the experimental technology of single-cell sequencing, revealed the specific mechanism of the occurrence of Crohn's disease caused by the loss of NOD2 function, and solved the problem.
A difficult problem in this field. More importantly, their mechanism research provides a new drug target for Crohn’s disease—gp130, which is undoubtedly worthwhile for Crohn’s patients, especially those who do not respond to anti-TNF therapy.
Looking forward to the good news.
Original link: https://doi.
org/10.
1038/s41586-021-03484-5 Platemaker: 11 References 1.
Ogura, Y.
et al.
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
Nature 41 , 603-606(2001).
2.
Martin, JC et al.
Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.
Cell 178, 1493-1508.
e20 (2019).
Reprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Among them, NOD2 loss-of-function mutations are considered to be an important risk factor for the occurrence of CD [1].
Although scientists have now realized that the imbalance of macrophage-fibroblast system homeostasis in the microenvironment caused by NOD2 loss-of-function mutations may be an important driving factor leading to the occurrence of CD [2], the specific pathogenicity of NOD2 loss Mechanism has always been an unresolved issue in this area.
Recently, Professor Judy H.
Cho’s research team from the Department of Genetics and Genomics of Icahn Medical College of Mount Sinai published a research article titled A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn's disease in the journal Nature, revealing The specific mechanism of the occurrence of Crohn’s disease caused by the loss of NOD2 function was found, and a new therapeutic target for Crohn’s disease was found.
First, the author identified a type of CD14+PDGFRA+ fibroblasts.
By comparing inflamed and non-inflamed ileum tissues, the authors found that CD14+PDGFRA+ cells in inflamed ileum tissues are rich in pro-fibrotic factors (such as WT1 and IL11).
Set.
NOD2 can sense the components of bacteria when infection occurs and is expressed in fibroblasts activated by inflammation.
Therefore, the authors speculate that the loss of NOD2 function may drive the abnormal differentiation of CD14+ peripheral blood mononuclear cells (PDMBs) to form fibrotic macrophages.
To verify this conjecture, the authors first analyzed PDMBs of normal (NOD2WT) and NOD2 mutations (NOD2MT) volunteers.
They found that as the copy number of NOD2 risk alleles increased, the expression levels of fibroblast genes in these cells also increased.
Increased accordingly.
Further, by verifying in wild-type (nod2wt), nod2 mutant (nod2sa21011) and nod2 knockout (nod2mss13) zebrafish, the authors once again proved that loss of NOD2 function does indeed increase pro-fibrosis-related transcription factors in an inflammatory state.
expression.
These experimental results indicate that the loss of NOD2 will reshape the fate of macrophages in an inflammatory state, making them a fibrotic phenotype.
In addition, the authors found that loss of NOD2 can aggravate the CD phenotype and lead to excessive activation of the transcription level of fibroblasts and pro-inflammatory macrophages.
So how does the loss of NOD2 affect the transcription levels of fibroblasts and pro-inflammatory macrophages? By analyzing the scRNAseq data of fibroblasts and macrophages from normal and NOD2 mutant volunteers, the authors found that in NOD2 mutant volunteers, STAT3 is enriched in both types of cells, and STAT3 increases pro-inflammatory /Transcription of pro-fibrotic factors, suggesting that STAT3 may play an important regulatory role in this process.
Therefore, the authors speculate that blocking the common cytokine receptor subunit gp130 upstream of STAT3 with the small molecule inhibitor bazedoxifene may inhibit the excessive activation of fibroblasts and pro-inflammatory macrophages in an inflammatory state.
Experimental results show that bazedoxifene can indeed inhibit the excessive activation of fibroblasts and pro-inflammatory macrophages, thereby reducing the DSS-induced enteritis phenotype.
In general, the research team used people with NOD2 mutations and zebrafish lacking nod2 as the research object, and using the experimental technology of single-cell sequencing, revealed the specific mechanism of the occurrence of Crohn's disease caused by the loss of NOD2 function, and solved the problem.
A difficult problem in this field. More importantly, their mechanism research provides a new drug target for Crohn’s disease—gp130, which is undoubtedly worthwhile for Crohn’s patients, especially those who do not respond to anti-TNF therapy.
Looking forward to the good news.
Original link: https://doi.
org/10.
1038/s41586-021-03484-5 Platemaker: 11 References 1.
Ogura, Y.
et al.
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
Nature 41 , 603-606(2001).
2.
Martin, JC et al.
Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.
Cell 178, 1493-1508.
e20 (2019).
Reprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.