Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01401-8
Eun Sun Lee, Hyeong Jae Kim, Dongun Lee, Jung Yun Kang, Dong Min Shin, Jeong Hee Hong
Fibroblast-like synoviocytes (FLSs) and osteoclasts are central cells in the maintenance of joint homeostasis. Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints that induces cytokine-activated FLSs and progressive bone erosion. Interactions between FLSs and other cells, such as T cells and B cells, have been recognized in the development of RA. Here we hypothesized that calcium released from bone by mature osteoclasts might activate FLSs, which are also affected by inflammatory cytokines in the inflamed synovium. Osteoclastogenesis occurs in the presence of cytokine-stimulated FLS medium, and calcium released from the bone disc activates FLS migration. We first investigated the calcium and cytokine feedback loop between FLSs and osteoclast maturation. Moreover, by addressing the role of the sodium-bicarbonate cotransporter NBCn1 in osteoclastogenesis, we found that the inhibition of NBCn1 attenuated the infinite calcium and cytokine feedback loop between FLSs and osteoclasts. In a collagen-induced arthritis mouse model, the inhibition of NBC reduced the RA pathological phenotype and bone resorption area in the femur. These results suggest that modulation of the crosstalk between FLSs and osteoclasts by inhibiting the calcium and cytokine feedback loop could be considered to develop pioneering strategies to combat RA severity and dysregulated bone homeostasis. Rheumatoid arthritis is a painful condition that damages joints and bones. Despite treatment advances, some patients do not respond well to current therapies. Researchers explored a new approach to address this issue. They focused on calcium and cytokines in RA. The study involved 16 patients and used mouse models to understand how these elements affect joint damage. The researchers found that Ca2+ from bones and inflammatory cytokines increase the activity of fibroblast-like synoviocytes, cells that contribute to joint damage. They discovered that inhibiting a protein called NBCn1, which helps cells move, could reduce this harmful activity. They used a drug called S0859 to block NBCn1 in RA-induced mice, which decreased bone damage and inflammation. The study suggests that targeting NBCn1 could be a new way to treat RA, especially for those who do not respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Rheumatoid arthritis severity is mediated by crosstalk between synoviocytes and mature osteoclasts through a calcium and cytokine feedback loop","authors":"Eun Sun Lee, Hyeong Jae Kim, Dongun Lee, Jung Yun Kang, Dong Min Shin, Jeong Hee Hong","doi":"10.1038/s12276-025-01401-8","DOIUrl":"10.1038/s12276-025-01401-8","url":null,"abstract":"Fibroblast-like synoviocytes (FLSs) and osteoclasts are central cells in the maintenance of joint homeostasis. Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints that induces cytokine-activated FLSs and progressive bone erosion. Interactions between FLSs and other cells, such as T cells and B cells, have been recognized in the development of RA. Here we hypothesized that calcium released from bone by mature osteoclasts might activate FLSs, which are also affected by inflammatory cytokines in the inflamed synovium. Osteoclastogenesis occurs in the presence of cytokine-stimulated FLS medium, and calcium released from the bone disc activates FLS migration. We first investigated the calcium and cytokine feedback loop between FLSs and osteoclast maturation. Moreover, by addressing the role of the sodium-bicarbonate cotransporter NBCn1 in osteoclastogenesis, we found that the inhibition of NBCn1 attenuated the infinite calcium and cytokine feedback loop between FLSs and osteoclasts. In a collagen-induced arthritis mouse model, the inhibition of NBC reduced the RA pathological phenotype and bone resorption area in the femur. These results suggest that modulation of the crosstalk between FLSs and osteoclasts by inhibiting the calcium and cytokine feedback loop could be considered to develop pioneering strategies to combat RA severity and dysregulated bone homeostasis. Rheumatoid arthritis is a painful condition that damages joints and bones. Despite treatment advances, some patients do not respond well to current therapies. Researchers explored a new approach to address this issue. They focused on calcium and cytokines in RA. The study involved 16 patients and used mouse models to understand how these elements affect joint damage. The researchers found that Ca2+ from bones and inflammatory cytokines increase the activity of fibroblast-like synoviocytes, cells that contribute to joint damage. They discovered that inhibiting a protein called NBCn1, which helps cells move, could reduce this harmful activity. They used a drug called S0859 to block NBCn1 in RA-induced mice, which decreased bone damage and inflammation. The study suggests that targeting NBCn1 could be a new way to treat RA, especially for those who do not respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"402-419"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01401-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01392-6
Mira Park, Yeon Sun Kim, Haengseok Song
Reproduction consists of sequential inflammation-like events, primarily within the endometrium, from ovulation to embryo implantation, decidualization and delivery. During the reproductive cycle, the endometrium repeatedly undergoes cyclic periods of proliferation, differentiation, tissue breakdown and repair without scarring. Owing to their phagocytic activity, macrophages, key players in innate immunity, are thought to play crucial roles in the endometrium. Endometrial macrophages actively participate in various stages of reproductive tissue remodeling, particularly during decidualization and pregnancy establishment. Traditionally considered simple bystanders that clear debris to prevent autoimmune responses in tissue homeostasis, macrophages are now recognized as main actors with broad functional plasticity that allows them to fine tune the balance between pro- and anti-inflammatory responses during tissue inflammation, remodeling and repair. Homeostatic balance is determined by the sum of various mediators produced by two distinctly polarized macrophage subpopulations. The biased polarization of tissue-resident macrophages may contribute to the pathogenesis of various diseases, such as inflammation and cancer. Thus, understanding how macrophages contribute to endometrial homeostasis is crucial for deciphering the underlying mechanisms of various reproductive disorders. Nanomedicines using extracellular vesicles, nanoparticles and noncoding RNAs have recently been applied to modulate macrophage polarization and alleviate disease phenotypes. Despite these advances, the functions of endometrial macrophages under physiological and pathophysiological conditions remain poorly understood, which complicates the development of targeted therapies. Here we update the current understanding of the homeostatic function of macrophages and the putative contribution of endometrial macrophage dysfunction to reproductive disorders in women, along with innovative molecular therapeutics to resolve this issue. Macrophages are a type of white blood cell that plays a key role in our immune system by engulfing and digesting harmful substances. This Review explores the diverse roles of macrophages beyond their basic immune functions, particularly in female reproduction. Researchers found that these cells are crucial for inflammation regulation and tissue repair. Macrophages can change their behavior based on signals from their environment, which is known as polarization. They can become either M1 or M2 types, depending on the situation. In female reproduction, macrophages help with processes such as menstruation, embryo implantation and pregnancy maintenance. The study concludes that understanding macrophage functions can lead to new treatments for reproductive issues. Future research may focus on using macrophage-targeted therapies to improve reproductive health and treat related diseases. This summary was initially drafted using artificial intelligence, then revised
{"title":"Macrophages: a double-edged sword in female reproduction and disorders","authors":"Mira Park, Yeon Sun Kim, Haengseok Song","doi":"10.1038/s12276-025-01392-6","DOIUrl":"10.1038/s12276-025-01392-6","url":null,"abstract":"Reproduction consists of sequential inflammation-like events, primarily within the endometrium, from ovulation to embryo implantation, decidualization and delivery. During the reproductive cycle, the endometrium repeatedly undergoes cyclic periods of proliferation, differentiation, tissue breakdown and repair without scarring. Owing to their phagocytic activity, macrophages, key players in innate immunity, are thought to play crucial roles in the endometrium. Endometrial macrophages actively participate in various stages of reproductive tissue remodeling, particularly during decidualization and pregnancy establishment. Traditionally considered simple bystanders that clear debris to prevent autoimmune responses in tissue homeostasis, macrophages are now recognized as main actors with broad functional plasticity that allows them to fine tune the balance between pro- and anti-inflammatory responses during tissue inflammation, remodeling and repair. Homeostatic balance is determined by the sum of various mediators produced by two distinctly polarized macrophage subpopulations. The biased polarization of tissue-resident macrophages may contribute to the pathogenesis of various diseases, such as inflammation and cancer. Thus, understanding how macrophages contribute to endometrial homeostasis is crucial for deciphering the underlying mechanisms of various reproductive disorders. Nanomedicines using extracellular vesicles, nanoparticles and noncoding RNAs have recently been applied to modulate macrophage polarization and alleviate disease phenotypes. Despite these advances, the functions of endometrial macrophages under physiological and pathophysiological conditions remain poorly understood, which complicates the development of targeted therapies. Here we update the current understanding of the homeostatic function of macrophages and the putative contribution of endometrial macrophage dysfunction to reproductive disorders in women, along with innovative molecular therapeutics to resolve this issue. Macrophages are a type of white blood cell that plays a key role in our immune system by engulfing and digesting harmful substances. This Review explores the diverse roles of macrophages beyond their basic immune functions, particularly in female reproduction. Researchers found that these cells are crucial for inflammation regulation and tissue repair. Macrophages can change their behavior based on signals from their environment, which is known as polarization. They can become either M1 or M2 types, depending on the situation. In female reproduction, macrophages help with processes such as menstruation, embryo implantation and pregnancy maintenance. The study concludes that understanding macrophage functions can lead to new treatments for reproductive issues. Future research may focus on using macrophage-targeted therapies to improve reproductive health and treat related diseases. This summary was initially drafted using artificial intelligence, then revised","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"285-297"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01392-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01398-0
Mingu Gordon Park, Jiwoon Lim, Daeun Kim, Won-Seok Lee, Bo-Eun Yoon, C. Justin Lee
Pharmacological suppression of γ-aminobutyric acid (GABA) transaminase (GABA-T), the sole GABA-degrading enzyme and a potential therapeutic target for treating brain disorders such as epilepsy, increases not only phasic inhibition but also tonic inhibition. However, the specific cellular source, neuromodulatory effects and potential therapeutic benefits of this enhanced tonic inhibition remain unexplored due to the lack of cell-type-specific gene manipulation studies. Here we report that the increase in tonic GABA currents observed after GABA-T suppression is predominantly due to increased tonic GABA release from astrocytes rather than action-potential-dependent synaptic GABA spillover. General GABA-T knockdown (KD) by a short hairpin RNA considerably increased tonic GABA currents in dentate granule cells, thereby enhancing tonic inhibition. An astrocyte-specific rescue of GABA-T following general GABA-T KD normalized the elevated tonic GABA currents to near control levels. Tetrodotoxin-insensitive tonic GABA currents were significantly increased after general GABA-T KD, whereas tetrodotoxin-sensitive tonic GABA currents showed no significant increase, suggesting that this enhanced tonic inhibition is primarily action-potential independent. General GABA-T KD reduced the spike probability of granule cells and impaired dorsal hippocampus-dependent spatial memory, which were fully reversed by astrocyte-specific GABA-T rescue. These findings suggest that suppressing astrocytic GABA-T may be sufficient to influence the excitatory/inhibitory balance in the brain and associated behaviors. Our study implies that the therapeutic benefits of pharmacological GABA-T suppression may be largely attributed to the modulation of astrocytic GABA-T and its impact on tonic GABA release from astrocytes. This study explores how boosting a specific brain process called tonic inhibition affects memory and brain function. Tonic inhibition involves a chemical called γ-aminobutyric acid (GABA) that helps downregulate brain activity. Researchers wanted to understand how blocking GABA degradation in brain cells called astrocytes affects this process. The study focused on the hippocampus, a brain area important for memory. Researchers used mice to test their ideas. They reduced the expression of an enzyme called GABA transaminase in astrocytes, which normally helps break down GABA. This reduction increased astrocytic GABA release, enhancing tonic inhibition and reducing brain cell activity. They found that this change impaired long-term memory but not short-term memory. The results suggest that astrocytic GABA transaminase plays a crucial role in controlling brain activity and memory. By manipulating this enzyme, scientists might develop new treatments for neurological disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Suppressing astrocytic GABA transaminase enhances tonic inhibition and weakens hippocampal spatial memory","authors":"Mingu Gordon Park, Jiwoon Lim, Daeun Kim, Won-Seok Lee, Bo-Eun Yoon, C. Justin Lee","doi":"10.1038/s12276-025-01398-0","DOIUrl":"10.1038/s12276-025-01398-0","url":null,"abstract":"Pharmacological suppression of γ-aminobutyric acid (GABA) transaminase (GABA-T), the sole GABA-degrading enzyme and a potential therapeutic target for treating brain disorders such as epilepsy, increases not only phasic inhibition but also tonic inhibition. However, the specific cellular source, neuromodulatory effects and potential therapeutic benefits of this enhanced tonic inhibition remain unexplored due to the lack of cell-type-specific gene manipulation studies. Here we report that the increase in tonic GABA currents observed after GABA-T suppression is predominantly due to increased tonic GABA release from astrocytes rather than action-potential-dependent synaptic GABA spillover. General GABA-T knockdown (KD) by a short hairpin RNA considerably increased tonic GABA currents in dentate granule cells, thereby enhancing tonic inhibition. An astrocyte-specific rescue of GABA-T following general GABA-T KD normalized the elevated tonic GABA currents to near control levels. Tetrodotoxin-insensitive tonic GABA currents were significantly increased after general GABA-T KD, whereas tetrodotoxin-sensitive tonic GABA currents showed no significant increase, suggesting that this enhanced tonic inhibition is primarily action-potential independent. General GABA-T KD reduced the spike probability of granule cells and impaired dorsal hippocampus-dependent spatial memory, which were fully reversed by astrocyte-specific GABA-T rescue. These findings suggest that suppressing astrocytic GABA-T may be sufficient to influence the excitatory/inhibitory balance in the brain and associated behaviors. Our study implies that the therapeutic benefits of pharmacological GABA-T suppression may be largely attributed to the modulation of astrocytic GABA-T and its impact on tonic GABA release from astrocytes. This study explores how boosting a specific brain process called tonic inhibition affects memory and brain function. Tonic inhibition involves a chemical called γ-aminobutyric acid (GABA) that helps downregulate brain activity. Researchers wanted to understand how blocking GABA degradation in brain cells called astrocytes affects this process. The study focused on the hippocampus, a brain area important for memory. Researchers used mice to test their ideas. They reduced the expression of an enzyme called GABA transaminase in astrocytes, which normally helps break down GABA. This reduction increased astrocytic GABA release, enhancing tonic inhibition and reducing brain cell activity. They found that this change impaired long-term memory but not short-term memory. The results suggest that astrocytic GABA transaminase plays a crucial role in controlling brain activity and memory. By manipulating this enzyme, scientists might develop new treatments for neurological disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"379-389"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01398-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01397-1
Veronika Bosáková, Ioanna Papatheodorou, Filip Kafka, Zuzana Tomášiková, Petros Kolovos, Marcela Hortová Kohoutková, Jan Frič
The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut–brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease. The gut–brain axis involves communication between the brain and the gut, which is important for maintaining gut health. Here the authors explored this by studying serotonin’s role in gut inflammation using a three-dimensional human cell model. They used intestinal organoids to mimic human gut conditions. These organoids were treated with serotonin and TNF to study their effects on gut cells and immune responses. The researchers found that serotonin reduced TNF-induced inflammation by altering gene expression related to immune cell movement. The study showed that serotonin can decrease the production of certain inflammatory signals in the gut, potentially reducing inflammation. This suggests that targeting serotonin could help treat inflammatory bowel disease (IBD). In conclusion, serotonin plays a role in controlling gut inflammation, offering insights into new treatments for IBD. Future research could explore serotonin’s broader impact on other inflammatory diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Serotonin attenuates tumor necrosis factor-induced intestinal inflammation by interacting with human mucosal tissue","authors":"Veronika Bosáková, Ioanna Papatheodorou, Filip Kafka, Zuzana Tomášiková, Petros Kolovos, Marcela Hortová Kohoutková, Jan Frič","doi":"10.1038/s12276-025-01397-1","DOIUrl":"10.1038/s12276-025-01397-1","url":null,"abstract":"The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut–brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease. The gut–brain axis involves communication between the brain and the gut, which is important for maintaining gut health. Here the authors explored this by studying serotonin’s role in gut inflammation using a three-dimensional human cell model. They used intestinal organoids to mimic human gut conditions. These organoids were treated with serotonin and TNF to study their effects on gut cells and immune responses. The researchers found that serotonin reduced TNF-induced inflammation by altering gene expression related to immune cell movement. The study showed that serotonin can decrease the production of certain inflammatory signals in the gut, potentially reducing inflammation. This suggests that targeting serotonin could help treat inflammatory bowel disease (IBD). In conclusion, serotonin plays a role in controlling gut inflammation, offering insights into new treatments for IBD. Future research could explore serotonin’s broader impact on other inflammatory diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"364-378"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01397-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01400-9
Jin Han, Yoon Hee Kim, Seungwoo Han
Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in the early stages of osteoarthritis (OA), but as the disease progresses, this metabolic adaptation becomes limited and eventually fails, leading to mitochondrial dysfunction and oxidative stress. Here we investigated whether enhancing OxPhos through the inhibition of pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in a surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro and in the articular cartilage of the DMM model in vivo, accompanied by an increase in phosphorylated PDH. Mice lacking PDK2 showed significant resistance to cartilage damage and reduced pain behaviors in the DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to increases in APT and the NAD+/NADH ratio. These metabolic changes were accompanied by a decrease in reactive oxygen species and senescence in chondrocytes, as well as an increase in the expression of antioxidant proteins such as NRF2 and HO-1 after IL-1β treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation without affecting the JNK, mTOR, AKT and NF-κB pathways. p38 MAPK signaling was critically involved in reactive oxygen species production under glycolysis-dominant conditions in chondrocytes. Our study provides a proof of concept for PDK2-mediated metabolic reprogramming toward OxPhos as a new therapeutic strategy for OA. Osteoarthritis is a common joint disease where cartilage breaks down, causing pain and stiffness. Chondrocytes, the cells in cartilage, usually rely on glycolysis for energy production. However, in early OA, they can switch to oxidative phosphorylation as an alternative energy pathway. This study aimed to see if modulating chondrocyte metabolism could slow OA progression. Researchers focused on PDK2, a protein that inactivates PDH, thereby reducing OxPhos activity in chondrocytes. They used mice genetically modified to lack PDK2 and compared them with normal mice with surgically induced OA. They found that, without PDK2, chondrocytes had better energy balance by using OxPhos more effectively and less oxidative stress, which slowed OA progression. This suggests that targeting PDK2 could be a new way to treat OA by improving chondrocyte metabolism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Increased oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in mice with surgically induced osteoarthritis","authors":"Jin Han, Yoon Hee Kim, Seungwoo Han","doi":"10.1038/s12276-025-01400-9","DOIUrl":"10.1038/s12276-025-01400-9","url":null,"abstract":"Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in the early stages of osteoarthritis (OA), but as the disease progresses, this metabolic adaptation becomes limited and eventually fails, leading to mitochondrial dysfunction and oxidative stress. Here we investigated whether enhancing OxPhos through the inhibition of pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in a surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro and in the articular cartilage of the DMM model in vivo, accompanied by an increase in phosphorylated PDH. Mice lacking PDK2 showed significant resistance to cartilage damage and reduced pain behaviors in the DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to increases in APT and the NAD+/NADH ratio. These metabolic changes were accompanied by a decrease in reactive oxygen species and senescence in chondrocytes, as well as an increase in the expression of antioxidant proteins such as NRF2 and HO-1 after IL-1β treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation without affecting the JNK, mTOR, AKT and NF-κB pathways. p38 MAPK signaling was critically involved in reactive oxygen species production under glycolysis-dominant conditions in chondrocytes. Our study provides a proof of concept for PDK2-mediated metabolic reprogramming toward OxPhos as a new therapeutic strategy for OA. Osteoarthritis is a common joint disease where cartilage breaks down, causing pain and stiffness. Chondrocytes, the cells in cartilage, usually rely on glycolysis for energy production. However, in early OA, they can switch to oxidative phosphorylation as an alternative energy pathway. This study aimed to see if modulating chondrocyte metabolism could slow OA progression. Researchers focused on PDK2, a protein that inactivates PDH, thereby reducing OxPhos activity in chondrocytes. They used mice genetically modified to lack PDK2 and compared them with normal mice with surgically induced OA. They found that, without PDK2, chondrocytes had better energy balance by using OxPhos more effectively and less oxidative stress, which slowed OA progression. This suggests that targeting PDK2 could be a new way to treat OA by improving chondrocyte metabolism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"390-401"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01400-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01396-2
Hyunsoo Kim, Channy Park, Xiaofan Wei, Arun Chhetri, Laxman Manandhar, Gyuho Jang, Jaetaek Hwang, Batchingis Chinbold, Chagtsalmaa Chuluunbaatar, Hyug Moo Kwon, Raekil Park
The breakdown of Golgi proteins disrupts lipid trafficking, leading to lipid accumulation in the small intestine. However, the causal mechanism of the effects of Golgi protein degradation on the Golgi structure related to lipid trafficking in the small intestine remains unknown. Here we find that Golgi protein degradation occurs under hypoxic conditions in high-fat-diet-fed mice. Hypoxia-induced degradation promotes structural changes in the Golgi apparatus, termed ‘Golgi condensation’. In addition, hypoxia-inducible factor 1α (HIF-1α) activation enhances Golgi condensation through the ubiquitination and degradation of Golgi matrix protein 130 (GM130), which is facilitated by neural precursor cell expressed developmentally downregulated protein 4 (NEDD4). Golgi condensation upon exposure to hypoxia promotes lipid accumulation, apolipoprotein A1 retention and decreased chylomicron secretion in the intestinal epithelium. Golgi condensation and lipid accumulation induced by GM130 depletion are reversed by exogenous GM130 induction in the intestinal epithelium. Inhibition of either HIF-1α or NEDD4 protects against GM130 degradation and, thereby, rescues cells from Golgi condensation, which further increases apolipoprotein A1 secretion and lipid accumulation both in vivo and in vitro. Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals. This study explores how low oxygen levels affect the Golgi apparatus, a cell structure involved in processing and packaging proteins and lipids. The study used mice and cell models to investigate these effects. They found that HIF-1α causes the Golgi apparatus to condense or shrink, which disrupts its function. This change is linked to increased lipid accumulation in the small intestine. The researchers discovered that HIF-1α plays a crucial role in this process by promoting the degradation of another protein, GM130, which is essential for maintaining Golgi structure, and NEDD4, a E3 ligase, which contributes on GM130 degradation. The findings suggest that preventing Golgi condensation by inhibiting HIF-1α could reduce lipid buildup in the obese intestine. This research provides new insights into how hypoxia affects lipid metabolism and could lead to potential treatments for obesity-related conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4","authors":"Hyunsoo Kim, Channy Park, Xiaofan Wei, Arun Chhetri, Laxman Manandhar, Gyuho Jang, Jaetaek Hwang, Batchingis Chinbold, Chagtsalmaa Chuluunbaatar, Hyug Moo Kwon, Raekil Park","doi":"10.1038/s12276-025-01396-2","DOIUrl":"10.1038/s12276-025-01396-2","url":null,"abstract":"The breakdown of Golgi proteins disrupts lipid trafficking, leading to lipid accumulation in the small intestine. However, the causal mechanism of the effects of Golgi protein degradation on the Golgi structure related to lipid trafficking in the small intestine remains unknown. Here we find that Golgi protein degradation occurs under hypoxic conditions in high-fat-diet-fed mice. Hypoxia-induced degradation promotes structural changes in the Golgi apparatus, termed ‘Golgi condensation’. In addition, hypoxia-inducible factor 1α (HIF-1α) activation enhances Golgi condensation through the ubiquitination and degradation of Golgi matrix protein 130 (GM130), which is facilitated by neural precursor cell expressed developmentally downregulated protein 4 (NEDD4). Golgi condensation upon exposure to hypoxia promotes lipid accumulation, apolipoprotein A1 retention and decreased chylomicron secretion in the intestinal epithelium. Golgi condensation and lipid accumulation induced by GM130 depletion are reversed by exogenous GM130 induction in the intestinal epithelium. Inhibition of either HIF-1α or NEDD4 protects against GM130 degradation and, thereby, rescues cells from Golgi condensation, which further increases apolipoprotein A1 secretion and lipid accumulation both in vivo and in vitro. Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals. This study explores how low oxygen levels affect the Golgi apparatus, a cell structure involved in processing and packaging proteins and lipids. The study used mice and cell models to investigate these effects. They found that HIF-1α causes the Golgi apparatus to condense or shrink, which disrupts its function. This change is linked to increased lipid accumulation in the small intestine. The researchers discovered that HIF-1α plays a crucial role in this process by promoting the degradation of another protein, GM130, which is essential for maintaining Golgi structure, and NEDD4, a E3 ligase, which contributes on GM130 degradation. The findings suggest that preventing Golgi condensation by inhibiting HIF-1α could reduce lipid buildup in the obese intestine. This research provides new insights into how hypoxia affects lipid metabolism and could lead to potential treatments for obesity-related conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"349-363"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01396-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1038/s12276-024-01383-z
Mansoor Hussain, Prabhat Khadka, Komal Pekhale, Tomasz Kulikowicz, Samuel Gray, Alfred May, Deborah L. Croteau, Vilhelm A. Bohr
RecQ helicases, highly conserved proteins with pivotal roles in DNA replication, DNA repair and homologous recombination, are crucial for maintaining genomic integrity. Mutations in RECQL4 have been associated with various human diseases, including Rothmund–Thomson syndrome. RECQL4 is involved in regulating major DNA repair pathways, such as homologous recombination and nonhomologous end joining (NHEJ). RECQL4 has more prominent single-strand DNA annealing activity than helicase activity. Its ability to promote DNA damage repair and the precise role of its DNA annealing activity in DNA repair are unclear. Here we demonstrate that PARP1 interacts with RECQL4, increasing its single-stranded DNA strand annealing activity. PARP1 specifically promoted RECQL4 PARylation at both its N- and C-terminal regions, promoting RECQL4 recruitment to DNA double-strand breaks (DSBs). Inhibition or depletion of PARP1 significantly diminished RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. After DNA damage, PARG dePARylated RECQL4 and stimulated its end-joining activity. RECQL4 actively displaced replication protein A from single-stranded DNA, promoting microhomology annealing in vitro. Furthermore, depletion of PARP1 or RECQL4 substantially impacted classical-NHEJ- and alternative-NHEJ-mediated DSB repair. Consequently, the combined activities of PARP1, PARG and RECQL4 modulate DNA repair. Cells have mechanisms to repair DNA damage, which is crucial for preventing diseases such as cancer. The authors wanted to understand how another protein, PARP1, affects the role of RECQL4 in DNA repair. The study involved laboratory experiments using human cells to see how RECQL4 and PARP1 interact. PARP1 helps recruit RECQL4 to sites of DNA damage and enhances its ability to repair DNA by promoting the strand annealing process. However, when RECQL4 is modified by PARP1 through PARylation, its repair activity is reduced. Another protein, PARG, can reverse this modification, restoring the function of RECQL4. The results suggest that the interaction between RECQL4 and PARP1 is important for efficient DNA repair. This understanding could lead to new strategies for treating diseases related to DNA repair defects, such as cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining","authors":"Mansoor Hussain, Prabhat Khadka, Komal Pekhale, Tomasz Kulikowicz, Samuel Gray, Alfred May, Deborah L. Croteau, Vilhelm A. Bohr","doi":"10.1038/s12276-024-01383-z","DOIUrl":"10.1038/s12276-024-01383-z","url":null,"abstract":"RecQ helicases, highly conserved proteins with pivotal roles in DNA replication, DNA repair and homologous recombination, are crucial for maintaining genomic integrity. Mutations in RECQL4 have been associated with various human diseases, including Rothmund–Thomson syndrome. RECQL4 is involved in regulating major DNA repair pathways, such as homologous recombination and nonhomologous end joining (NHEJ). RECQL4 has more prominent single-strand DNA annealing activity than helicase activity. Its ability to promote DNA damage repair and the precise role of its DNA annealing activity in DNA repair are unclear. Here we demonstrate that PARP1 interacts with RECQL4, increasing its single-stranded DNA strand annealing activity. PARP1 specifically promoted RECQL4 PARylation at both its N- and C-terminal regions, promoting RECQL4 recruitment to DNA double-strand breaks (DSBs). Inhibition or depletion of PARP1 significantly diminished RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. After DNA damage, PARG dePARylated RECQL4 and stimulated its end-joining activity. RECQL4 actively displaced replication protein A from single-stranded DNA, promoting microhomology annealing in vitro. Furthermore, depletion of PARP1 or RECQL4 substantially impacted classical-NHEJ- and alternative-NHEJ-mediated DSB repair. Consequently, the combined activities of PARP1, PARG and RECQL4 modulate DNA repair. Cells have mechanisms to repair DNA damage, which is crucial for preventing diseases such as cancer. The authors wanted to understand how another protein, PARP1, affects the role of RECQL4 in DNA repair. The study involved laboratory experiments using human cells to see how RECQL4 and PARP1 interact. PARP1 helps recruit RECQL4 to sites of DNA damage and enhances its ability to repair DNA by promoting the strand annealing process. However, when RECQL4 is modified by PARP1 through PARylation, its repair activity is reduced. Another protein, PARG, can reverse this modification, restoring the function of RECQL4. The results suggest that the interaction between RECQL4 and PARP1 is important for efficient DNA repair. This understanding could lead to new strategies for treating diseases related to DNA repair defects, such as cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 1","pages":"264-280"},"PeriodicalIF":9.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01383-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1038/s12276-024-01389-7
Haoyu Ji, Wenya Ma, Xu Liu, Hongyang Chen, Yining Liu, Zhongyu Ren, Daohong Yin, Ao Cai, Zizhen Zhang, Xin Wang, Wei Huang, Leping Shi, Yanan Tian, Yang Yu, Xiuxiu Wang, Yang Li, Yu Liu, Benzhi Cai
Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies. Doxorubicin is a powerful cancer drug, but it can harm the heart, leading to a condition called doxorubicin-induced cardiotoxicity (DIC). Some people are more affected by DIC than others, and scientists want to understand why. They found that the heterogeneity observed among endothelial cells (ECs) plays a potential role in determining DIC sensitivity. In mice less sensitive to DIC, reprogramming of ECs increases levels of P-glycoprotein (P-gp), which helps to pump drugs out of cells. They discovered that activating a pathway involving IFN-γ increased P-gp levels, reducing heart damage. Conversely, activating another pathway, PPAR-γ, decreased P-gp levels and increased heart damage. These findings provide new insights into DIC pathogenesis and suggest that boosting P-gp in ECs could be a new strategy to protect against DIC. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity","authors":"Haoyu Ji, Wenya Ma, Xu Liu, Hongyang Chen, Yining Liu, Zhongyu Ren, Daohong Yin, Ao Cai, Zizhen Zhang, Xin Wang, Wei Huang, Leping Shi, Yanan Tian, Yang Yu, Xiuxiu Wang, Yang Li, Yu Liu, Benzhi Cai","doi":"10.1038/s12276-024-01389-7","DOIUrl":"10.1038/s12276-024-01389-7","url":null,"abstract":"Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies. Doxorubicin is a powerful cancer drug, but it can harm the heart, leading to a condition called doxorubicin-induced cardiotoxicity (DIC). Some people are more affected by DIC than others, and scientists want to understand why. They found that the heterogeneity observed among endothelial cells (ECs) plays a potential role in determining DIC sensitivity. In mice less sensitive to DIC, reprogramming of ECs increases levels of P-glycoprotein (P-gp), which helps to pump drugs out of cells. They discovered that activating a pathway involving IFN-γ increased P-gp levels, reducing heart damage. Conversely, activating another pathway, PPAR-γ, decreased P-gp levels and increased heart damage. These findings provide new insights into DIC pathogenesis and suggest that boosting P-gp in ECs could be a new strategy to protect against DIC. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 1","pages":"249-263"},"PeriodicalIF":9.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01389-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1038/s12276-024-01388-8
Chae-Jeong Lee, Seung Hyun Jang, Jiwoo Lim, Hyunju Park, So-Hee Ahn, Seon Young Park, Hyangmi Seo, Soo-Jin Song, Jung-A Shin, Chulhee Choi, Heon Yung Gee, Youn-Hee Choi
Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation. As we age, our bodies undergo changes that can lead to diseases like Alzheimer’s and Parkinson’s. A key factor in this process is inflammation in the brain, driven by a protein called NF-κB. Researcher explored a new way to reduce this inflammation using tiny particles called exosomes. These exosomes were engineered to carry a special form of a protein that blocks NF-κB, called srIκB. In their study, the team injected these exosomes into mice and observed their effects on neuroinflammation. They used advanced techniques to analyze changes in cells of the brain and found that the exosomes reduced inflammation-related genes and altered immune cell behavior. This suggests that the exosomes can help control inflammation in the aging brain. The results indicate that these engineered exosomes could be a promising treatment for age-related brain diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
神经炎症是各种神经退行性疾病的重要诱因，与衰老过程密切相关；然而，到目前为止，还没有有效的治疗神经炎症的方法。在老年小鼠大脑中，浸润的免疫细胞数量增加，与趋化因子水平增加相关的关键转录因子是核因子κB （NF-κB）。外泌体是多种物质（包括蛋白质和调控基因）靶向细胞的有效疗法或药物递送载体。在本研究中，我们评估了装载不可降解形式的i -κB （exo - sri -κB）的外泌体的治疗效果，该外泌体抑制NF-κB的核易位以抑制年龄相关的神经炎症。单细胞RNA测序显示，这些抗炎外泌体靶向巨噬细胞和小胶质细胞，降低炎症相关基因的表达。用Exo-srIκB治疗也抑制了巨噬细胞/小胶质细胞与老年脑内T细胞和B细胞的相互作用。我们证明，Exo-srIκB通过主要靶向活化的巨噬细胞和部分调节大脑中年龄相关的干扰素反应性小胶质细胞的功能，成功地减轻了神经炎症。因此，我们的研究结果强调了Exo-srIκB作为治疗年龄相关性神经炎症的潜在治疗剂。
{"title":"Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain","authors":"Chae-Jeong Lee, Seung Hyun Jang, Jiwoo Lim, Hyunju Park, So-Hee Ahn, Seon Young Park, Hyangmi Seo, Soo-Jin Song, Jung-A Shin, Chulhee Choi, Heon Yung Gee, Youn-Hee Choi","doi":"10.1038/s12276-024-01388-8","DOIUrl":"10.1038/s12276-024-01388-8","url":null,"abstract":"Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation. As we age, our bodies undergo changes that can lead to diseases like Alzheimer’s and Parkinson’s. A key factor in this process is inflammation in the brain, driven by a protein called NF-κB. Researcher explored a new way to reduce this inflammation using tiny particles called exosomes. These exosomes were engineered to carry a special form of a protein that blocks NF-κB, called srIκB. In their study, the team injected these exosomes into mice and observed their effects on neuroinflammation. They used advanced techniques to analyze changes in cells of the brain and found that the exosomes reduced inflammation-related genes and altered immune cell behavior. This suggests that the exosomes can help control inflammation in the aging brain. The results indicate that these engineered exosomes could be a promising treatment for age-related brain diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 1","pages":"235-248"},"PeriodicalIF":9.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01388-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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