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Editor | Enzyme beauty rheumatoid arthritis is an autoimmune disease with complex etiology.
The characteristic pathological changes are joint synovial inflammation and pannus formation, leading to articular cartilage and bone erosion
.
Although biological therapies targeting the cytokines TNF- and IL-6 can effectively control inflammation and delay the progression of joint damage, they cannot completely prevent progressive joint erosion and cannot achieve clinical cure
.
Activated synovial fibroblasts are one of the main effector cells of the proliferating synovium, and their production of inflammatory cytokines, pro-angiogenic factors and matrix hydrolase promotes inflammation, angiogenesis and matrix degradation, and is an important mechanism for bone destruction.
.
Therefore, the development of new therapies targeting activated synovial fibroblasts is of great significance for the treatment of rheumatoid arthritis
.
Recently, the team of Professor Zhu Ping, Department of Clinical Immunology, Xijing Hospital, Air Force Military Medical University published a research work entitled TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models in the journal Nature Communications, and found that in the progression of rheumatoid arthritis , tumor necrosis factor TNF is a key signal regulating the resistance to ferroptosis in synovial fibroblasts
.
TNF promotes glutathione (GSH) biosynthesis in cells by activating NF-κB, protecting fibroblasts from lipid peroxidative stress and against ferroptosis
.
The TNF antagonist etanercept can significantly enhance the killing effect of low-dose ferroptosis inducer IKE on fibroblasts, thereby alleviating joint inflammation and cartilage destruction, and inhibiting the progression of rheumatoid arthritis
.
Ferroptosis is a novel form of programmed cell death that is iron-dependent and caused by the accumulation of lipid reactive oxygen species (lipid ROS) in cells, and is tightly regulated by intracellular signaling pathways
.
Free Fe2+ in cells generates reactive oxygen radicals through Fenton reaction, or induces membrane lipid polyunsaturated fatty acid oxidation by participating in enzymatic reactions
.
At the same time, there are protective mechanisms against lipid peroxidative damage in cells, such as glutathione peroxidase (GPX4), coenzyme Q oxidoreductase (FSP1),
etc.
When lipid ROS is over-produced in cells and protective pathways such as GPX4 are inactivated, the accumulated lipid ROS will disrupt membrane permeability and stability, and eventually induce ferroptosis
.
The study found that compared with osteoarthritis, rheumatoid arthritis synovial tissue and synovial fluid have ferroptosis-related phenomena such as increased lipid peroxidation products and increased iron load, but synovial fibroblasts can be abundant Cascade proliferation, showing a tumor cell-like growth state
.
The same phenomenon was found in a mouse model of collagen-induced arthritis (CIA)
.
Although pretreatment with the ferroptosis inhibitor liproxstatin-1 significantly suppressed the onset of inflammatory symptoms in the CIA model, it did not alleviate arthritis progression when administered after active inflammation
.
Conversely, administration of high-dose ferroptosis inducer IKE after the onset of inflammation reduced the number of fibroblast-activated protein alpha (FAPα+) fibroblasts in synovial tissue and effectively attenuated the progression of inflammation
.
Single-cell transcriptome analysis found that FAPα+ fibroblasts contained two subpopulations with marked differences in ferroptosis responses
.
After low-dose IKE treatment of CIA mice, the positive proportion of ferroptosis-sensitive subset (mfap4+) in FAPα+ synovial fibroblasts was significantly reduced, while the positive proportion of ferroptosis-inhibited subset (Sparcl1+) did not change significantly
.
Gene enrichment GSEA analysis revealed that the two subpopulations differed in function
.
Predicted ferroptosis-sensitive subsets showed significant gene enrichment in pathways related to extracellular matrix formation and remodeling, while predicted ferroptosis-resistant subsets of genes were enriched in proliferation and cell cycle-related pathways
.
KEGG enrichment analysis found that TNF signaling was significantly activated in ferroptosis-induced resistant fibroblast subsets
.
As one of the most abundant cell types in the rheumatoid arthritis synovium, macrophages constitute a major source of the proinflammatory cytokine TNF
.
The authors performed single-cell sequencing of the hyperplastic synovium of patients with rheumatoid arthritis to further analyze the transduction of TNF signaling between macrophages and fibroblasts
.
By comparing pathway activities, fibroblasts were divided into two subpopulations, in which the TNF-NF-κB signal-enriched subpopulation showed higher expression of ferroptosis resistance subpopulation marker genes
.
Analysis of cellular communication networks found that receptor-ligand pair interactions between macrophages and potentially ferroptosis-resistant fibroblast subsets were more pronounced
.
These results suggest that TNF signaling from macrophages may regulate ferroptosis sensitivity in a subset of fibroblasts
.
To further elucidate the specific mechanisms underlying the regulation of ferroptosis sensitivity in synovial fibroblasts, the authors stimulated primary human synovial fibroblasts with TNF and examined cellular responses to the classical ferroptosis inducers IKE and RSL3
.
Studies have found that TNF can protect synovial fibroblasts against the effects of IKE and low-dose RSL3, while high-dose RSL3 can still induce lipid ROS production and ferroptosis in the presence of TNF
.
As a fully human TNF monoclonal antibody approved for the treatment of rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease, adalimumab can effectively inhibit the protective effect of TNF on synovial fibroblast ferroptosis role
.
Mechanistically, TNF upregulates the cystine-glutamate antiporter (xCT) subunit SLC7A11, as well as the glutamate-cysteine ligase catalytic subunit (GCLM) and regulatory subunit of NF-κB by activating NF-κB.
GCLC expression, thereby promoting glutathione biosynthesis in cells, protecting fibroblasts from lipid peroxidative stress and resisting ferroptosis
.
Etanercept is a TNF antagonist used to treat inflammatory diseases, including rheumatoid arthritis, that specifically blocks the interaction of TNF-α with cell surface TNF-α receptors
.
The authors found that low-dose IKE combined with TNF blockade disrupted TNF-induced protection against ferroptosis and caused synovial fibroblast death in a mouse model of CIA
.
Following active inflammation in a mouse model treated with low-dose etanercept and low-dose IKE, etanercept in combination with IKE was found to reduce the severity of synovial inflammation and halt disease progression
.
The combination regimen also alleviated cartilage and bone damage and significantly reduced the number of FAPα+ fibroblasts, confirming that TNF inhibition enhanced the sensitivity of fibroblasts to IKE deprivation of cystine-induced ferroptosis
.
The authors stained the major organs of IKE-treated CIA mice, including heart, liver, spleen, lung, and kidney, and found that low-dose IKE did not cause obvious pathological changes in major organs, but long-term ferroptosis-induced inflammation could not be ruled out and risk of normal tissue damage
.
Therefore, ferroptosis strategies targeting fibroblasts are very necessary
.
The authors say that follow-up studies may identify more specific fibroblast surface markers, which will aid in the development of fibroblast-targeted ferroptosis therapeutic strategies
.
In addition, the FDA-approved rheumatoid arthritis drug sulfasalazine has also been shown to be effective in triggering ferroptosis, and will be combined with anti-TNF therapy to reduce the risk of ferroptosis-induced normal tissue damage
.
In cancer therapy, ferroptosis, as a form of non-apoptotic cell death, has gradually emerged as a new strategy to eliminate apoptosis-resistant tumor cells
.
However, whether ferroptosis induction therapy can play a role in the treatment of other diseases has not been fully elucidated
.
Abnormal fibrotic changes can occur in multiple organs, such as lung, liver, kidney, skin, etc.
, interfering with or inhibiting the normal structure and function of organs.
Excessive proliferation of fibroblasts leading to extracellular matrix deposition is a common feature of fibrotic changes.
.
Therefore, ferroptosis not only targets rheumatoid arthritis, but also provides evidence for the development of therapies that selectively target fibroblast subsets, and is expected to be a potential treatment for a variety of fibroblast dysregulation-related diseases, with important basic research and clinical value
.
Professor Zhu Ping of Xijing Hospital of Air Force Military Medical University is the corresponding author of the paper, and Professor Wu Jiao of the National Molecular Medicine Translation Center of Air Force Military Medical University is the first author of the paper
.
Link to the original text: https://pubmed.
ncbi.
nlm.
nih.
gov/35115492/ Publisher: 11 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
Possess all legal rights, and violators will be prosecuted
.
The characteristic pathological changes are joint synovial inflammation and pannus formation, leading to articular cartilage and bone erosion
.
Although biological therapies targeting the cytokines TNF- and IL-6 can effectively control inflammation and delay the progression of joint damage, they cannot completely prevent progressive joint erosion and cannot achieve clinical cure
.
Activated synovial fibroblasts are one of the main effector cells of the proliferating synovium, and their production of inflammatory cytokines, pro-angiogenic factors and matrix hydrolase promotes inflammation, angiogenesis and matrix degradation, and is an important mechanism for bone destruction.
.
Therefore, the development of new therapies targeting activated synovial fibroblasts is of great significance for the treatment of rheumatoid arthritis
.
Recently, the team of Professor Zhu Ping, Department of Clinical Immunology, Xijing Hospital, Air Force Military Medical University published a research work entitled TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models in the journal Nature Communications, and found that in the progression of rheumatoid arthritis , tumor necrosis factor TNF is a key signal regulating the resistance to ferroptosis in synovial fibroblasts
.
TNF promotes glutathione (GSH) biosynthesis in cells by activating NF-κB, protecting fibroblasts from lipid peroxidative stress and against ferroptosis
.
The TNF antagonist etanercept can significantly enhance the killing effect of low-dose ferroptosis inducer IKE on fibroblasts, thereby alleviating joint inflammation and cartilage destruction, and inhibiting the progression of rheumatoid arthritis
.
Ferroptosis is a novel form of programmed cell death that is iron-dependent and caused by the accumulation of lipid reactive oxygen species (lipid ROS) in cells, and is tightly regulated by intracellular signaling pathways
.
Free Fe2+ in cells generates reactive oxygen radicals through Fenton reaction, or induces membrane lipid polyunsaturated fatty acid oxidation by participating in enzymatic reactions
.
At the same time, there are protective mechanisms against lipid peroxidative damage in cells, such as glutathione peroxidase (GPX4), coenzyme Q oxidoreductase (FSP1),
etc.
When lipid ROS is over-produced in cells and protective pathways such as GPX4 are inactivated, the accumulated lipid ROS will disrupt membrane permeability and stability, and eventually induce ferroptosis
.
The study found that compared with osteoarthritis, rheumatoid arthritis synovial tissue and synovial fluid have ferroptosis-related phenomena such as increased lipid peroxidation products and increased iron load, but synovial fibroblasts can be abundant Cascade proliferation, showing a tumor cell-like growth state
.
The same phenomenon was found in a mouse model of collagen-induced arthritis (CIA)
.
Although pretreatment with the ferroptosis inhibitor liproxstatin-1 significantly suppressed the onset of inflammatory symptoms in the CIA model, it did not alleviate arthritis progression when administered after active inflammation
.
Conversely, administration of high-dose ferroptosis inducer IKE after the onset of inflammation reduced the number of fibroblast-activated protein alpha (FAPα+) fibroblasts in synovial tissue and effectively attenuated the progression of inflammation
.
Single-cell transcriptome analysis found that FAPα+ fibroblasts contained two subpopulations with marked differences in ferroptosis responses
.
After low-dose IKE treatment of CIA mice, the positive proportion of ferroptosis-sensitive subset (mfap4+) in FAPα+ synovial fibroblasts was significantly reduced, while the positive proportion of ferroptosis-inhibited subset (Sparcl1+) did not change significantly
.
Gene enrichment GSEA analysis revealed that the two subpopulations differed in function
.
Predicted ferroptosis-sensitive subsets showed significant gene enrichment in pathways related to extracellular matrix formation and remodeling, while predicted ferroptosis-resistant subsets of genes were enriched in proliferation and cell cycle-related pathways
.
KEGG enrichment analysis found that TNF signaling was significantly activated in ferroptosis-induced resistant fibroblast subsets
.
As one of the most abundant cell types in the rheumatoid arthritis synovium, macrophages constitute a major source of the proinflammatory cytokine TNF
.
The authors performed single-cell sequencing of the hyperplastic synovium of patients with rheumatoid arthritis to further analyze the transduction of TNF signaling between macrophages and fibroblasts
.
By comparing pathway activities, fibroblasts were divided into two subpopulations, in which the TNF-NF-κB signal-enriched subpopulation showed higher expression of ferroptosis resistance subpopulation marker genes
.
Analysis of cellular communication networks found that receptor-ligand pair interactions between macrophages and potentially ferroptosis-resistant fibroblast subsets were more pronounced
.
These results suggest that TNF signaling from macrophages may regulate ferroptosis sensitivity in a subset of fibroblasts
.
To further elucidate the specific mechanisms underlying the regulation of ferroptosis sensitivity in synovial fibroblasts, the authors stimulated primary human synovial fibroblasts with TNF and examined cellular responses to the classical ferroptosis inducers IKE and RSL3
.
Studies have found that TNF can protect synovial fibroblasts against the effects of IKE and low-dose RSL3, while high-dose RSL3 can still induce lipid ROS production and ferroptosis in the presence of TNF
.
As a fully human TNF monoclonal antibody approved for the treatment of rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease, adalimumab can effectively inhibit the protective effect of TNF on synovial fibroblast ferroptosis role
.
Mechanistically, TNF upregulates the cystine-glutamate antiporter (xCT) subunit SLC7A11, as well as the glutamate-cysteine ligase catalytic subunit (GCLM) and regulatory subunit of NF-κB by activating NF-κB.
GCLC expression, thereby promoting glutathione biosynthesis in cells, protecting fibroblasts from lipid peroxidative stress and resisting ferroptosis
.
Etanercept is a TNF antagonist used to treat inflammatory diseases, including rheumatoid arthritis, that specifically blocks the interaction of TNF-α with cell surface TNF-α receptors
.
The authors found that low-dose IKE combined with TNF blockade disrupted TNF-induced protection against ferroptosis and caused synovial fibroblast death in a mouse model of CIA
.
Following active inflammation in a mouse model treated with low-dose etanercept and low-dose IKE, etanercept in combination with IKE was found to reduce the severity of synovial inflammation and halt disease progression
.
The combination regimen also alleviated cartilage and bone damage and significantly reduced the number of FAPα+ fibroblasts, confirming that TNF inhibition enhanced the sensitivity of fibroblasts to IKE deprivation of cystine-induced ferroptosis
.
The authors stained the major organs of IKE-treated CIA mice, including heart, liver, spleen, lung, and kidney, and found that low-dose IKE did not cause obvious pathological changes in major organs, but long-term ferroptosis-induced inflammation could not be ruled out and risk of normal tissue damage
.
Therefore, ferroptosis strategies targeting fibroblasts are very necessary
.
The authors say that follow-up studies may identify more specific fibroblast surface markers, which will aid in the development of fibroblast-targeted ferroptosis therapeutic strategies
.
In addition, the FDA-approved rheumatoid arthritis drug sulfasalazine has also been shown to be effective in triggering ferroptosis, and will be combined with anti-TNF therapy to reduce the risk of ferroptosis-induced normal tissue damage
.
In cancer therapy, ferroptosis, as a form of non-apoptotic cell death, has gradually emerged as a new strategy to eliminate apoptosis-resistant tumor cells
.
However, whether ferroptosis induction therapy can play a role in the treatment of other diseases has not been fully elucidated
.
Abnormal fibrotic changes can occur in multiple organs, such as lung, liver, kidney, skin, etc.
, interfering with or inhibiting the normal structure and function of organs.
Excessive proliferation of fibroblasts leading to extracellular matrix deposition is a common feature of fibrotic changes.
.
Therefore, ferroptosis not only targets rheumatoid arthritis, but also provides evidence for the development of therapies that selectively target fibroblast subsets, and is expected to be a potential treatment for a variety of fibroblast dysregulation-related diseases, with important basic research and clinical value
.
Professor Zhu Ping of Xijing Hospital of Air Force Military Medical University is the corresponding author of the paper, and Professor Wu Jiao of the National Molecular Medicine Translation Center of Air Force Military Medical University is the first author of the paper
.
Link to the original text: https://pubmed.
ncbi.
nlm.
nih.
gov/35115492/ Publisher: 11 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
Possess all legal rights, and violators will be prosecuted
.
