Ling Li, Ping-Ping Gao, Ting-Ting Chen, Nan Li, Hui-Juan Zhang, Meng-Qi Li, Ya-Ning Chen, Wei Wei, Hua Wang, Wu-Yi Sun
Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases.
{"title":"SUMO: A new perspective to decipher fibrosis","authors":"Ling Li, Ping-Ping Gao, Ting-Ting Chen, Nan Li, Hui-Juan Zhang, Meng-Qi Li, Ya-Ning Chen, Wei Wei, Hua Wang, Wu-Yi Sun","doi":"10.1111/apha.14240","DOIUrl":"10.1111/apha.14240","url":null,"abstract":"<p>Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Endothelins are peptide hormones best known for their function in the regulation of vessel tone. They are mainly secreted by endothelial cells, but expression has been reported for many other tissues including liver, muscle, adipose tissues, and the brain.<span><sup>1</sup></span> The main of the three endothelin isoforms, endothelin-1 (ET-1), is the most potent natural vasoconstrictor known so far and has been implicated in a broad range of cardiovascular diseases. Interestingly, increased ET-1 levels are also reported in obese and diabetic patients, and ET-1 signaling through one of its two receptors, endothelin receptor beta (ET<sub>B</sub>), has been implicated in the regulation of insulin action and glucose homeostasis.</p><p>In this issue, Rivera-Gonzalez and co-workers studied the metabolic function of ET-1/ET<sub>B</sub> signaling in a mouse model of diet-induced obesity.<span><sup>2</sup></span> Their data suggest that ET-1-induced ET<sub>B</sub> signaling in adipose tissues inhibits the expression and release of the adipokine hormone adiponectin. This, in turn, is a well-known sensitizer of insulin signaling and glucose import and metabolization in tissues, such as adipose, muscle, and liver.<span><sup>3</sup></span> The new data offer an intriguing mechanistic explanation for the metabolic function of ET-1 signaling: obesity-induced upregulation of ET-1 expression leads to ET<sub>B</sub>-mediated downregulation of adiponectin release from adipocytes. Diminished adiponectin levels in the circulation, in turn, would desensitize insulin signaling and glucose disposal in target tissues promoting hyperglycemia and the development of insulin resistance (Figure 1).</p><p>The authors of this study provide several lines of evidence supporting their conclusions. First, they studied metabolic responses to ET-1 treatment in primary adipocytes upon genetic or pharmacological inhibition of ET<sub>B</sub> signaling. They show that ET-1 downregulates expression of the master metabolic transcriptional regulator, peroxisome proliferator-activated receptor gamma (<i>Pparγ</i>), and adiponectin (<i>Adipoq</i>). Second, they generated mice that specifically carry a knockout of or overexpress ET<sub>B</sub> in adipose tissue. By adipose tissue RNA-sequencing, they show that genes associated with metabolic pathways like insulin and adipokine signaling are upregulated in ET<sub>B</sub> knockout animals under high-fat-diet conditions. These include insulin receptor 1 (<i>Irs-1</i>), the insulin-dependent glucose transporter GLUT4 (<i>Slc2a4</i>), and adiponectin (<i>Adipoq</i>). Effects on other adipokines such as leptin and adipsin were also observed suggesting a pro-obesogenic action of ET-1 in adipose tissue. These effects were more pronounced in—hormonally more active—visceral compared to subcutaneous adipose depots. Finally, knockout of ET<sub>B</sub> improved insulin sensitivity and glucose handling in obese animals, while ET<sub>B</sub> overexpressio
{"title":"Adipose endothelin signaling—An unusual suspect linking obesity to insulin resistance","authors":"Henrik Oster","doi":"10.1111/apha.14241","DOIUrl":"10.1111/apha.14241","url":null,"abstract":"<p>Endothelins are peptide hormones best known for their function in the regulation of vessel tone. They are mainly secreted by endothelial cells, but expression has been reported for many other tissues including liver, muscle, adipose tissues, and the brain.<span><sup>1</sup></span> The main of the three endothelin isoforms, endothelin-1 (ET-1), is the most potent natural vasoconstrictor known so far and has been implicated in a broad range of cardiovascular diseases. Interestingly, increased ET-1 levels are also reported in obese and diabetic patients, and ET-1 signaling through one of its two receptors, endothelin receptor beta (ET<sub>B</sub>), has been implicated in the regulation of insulin action and glucose homeostasis.</p><p>In this issue, Rivera-Gonzalez and co-workers studied the metabolic function of ET-1/ET<sub>B</sub> signaling in a mouse model of diet-induced obesity.<span><sup>2</sup></span> Their data suggest that ET-1-induced ET<sub>B</sub> signaling in adipose tissues inhibits the expression and release of the adipokine hormone adiponectin. This, in turn, is a well-known sensitizer of insulin signaling and glucose import and metabolization in tissues, such as adipose, muscle, and liver.<span><sup>3</sup></span> The new data offer an intriguing mechanistic explanation for the metabolic function of ET-1 signaling: obesity-induced upregulation of ET-1 expression leads to ET<sub>B</sub>-mediated downregulation of adiponectin release from adipocytes. Diminished adiponectin levels in the circulation, in turn, would desensitize insulin signaling and glucose disposal in target tissues promoting hyperglycemia and the development of insulin resistance (Figure 1).</p><p>The authors of this study provide several lines of evidence supporting their conclusions. First, they studied metabolic responses to ET-1 treatment in primary adipocytes upon genetic or pharmacological inhibition of ET<sub>B</sub> signaling. They show that ET-1 downregulates expression of the master metabolic transcriptional regulator, peroxisome proliferator-activated receptor gamma (<i>Pparγ</i>), and adiponectin (<i>Adipoq</i>). Second, they generated mice that specifically carry a knockout of or overexpress ET<sub>B</sub> in adipose tissue. By adipose tissue RNA-sequencing, they show that genes associated with metabolic pathways like insulin and adipokine signaling are upregulated in ET<sub>B</sub> knockout animals under high-fat-diet conditions. These include insulin receptor 1 (<i>Irs-1</i>), the insulin-dependent glucose transporter GLUT4 (<i>Slc2a4</i>), and adiponectin (<i>Adipoq</i>). Effects on other adipokines such as leptin and adipsin were also observed suggesting a pro-obesogenic action of ET-1 in adipose tissue. These effects were more pronounced in—hormonally more active—visceral compared to subcutaneous adipose depots. Finally, knockout of ET<sub>B</sub> improved insulin sensitivity and glucose handling in obese animals, while ET<sub>B</sub> overexpressio","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386490","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}
Bertil Karlmark, Örjan Källskog, Peter Hansell, Mikael Broman, Mats Sjöquist
<p> </p><p>It is with great sadness that we announce to the renal community the passing of Professor emeritus in Physiology Mats Wolgast, Uppsala, Sweden. The closest mourners are the children Charlotta from his marriage to the late Inger Söder Wolgast, and Björn and Åsa from his previous marriage. He died after a period of illness at the age of 89.</p><p>Mats grew up in Bräkne-Hoby, a small town in the county of Blekinge, graduated in Helsingborg and studied medicine in Uppsala. He was instantly hooked on the subject of physiology and remained at the Department of Physiology in Uppsala after his medical studies where he graduated as a PhD in 1968.</p><p>Mats was a genius with the ability to see context and consequences long before the rest of us. The kidney became his main interest and the thesis in 1968 concerned the distribution of blood within the kidney with focus on the medulla with the essence being published in Nature<span><sup>1</sup></span> and Acta Physiologica Scandinavica.<span><sup>2</sup></span> A special room was built at the Biomedical Center for his research with radioactive red blood cells and tailored semiconductor detectors. When the work received a lot of international attention, he became a leading figure in the successful Kidney Research Group whose PhD students were welcomed at many research centers worldwide. He also studied permeability characteristics of charged biological membranes and the interstitial space using complicated mathematical models to explain the gel concept<span><sup>3</sup></span> which probably interfered with the ability to sleep of several referees and journal editors. Some even say he invented his own mathematics. He was also well known for his studies in revealing the dynamics of glomerular filtration.<span><sup>4</sup></span></p><p>Doctors in internal medicine, surgery, radiology, and nephrology approached Mats not only for help but also for collaboration. The need and existence of a sharp theoretical and practical physiologist became the foundation for a large number of clinical dissertations in a variety of fields such as ischemia–reperfusion injury, transplantation, acute kidney injury, and oxidative stress. His last publication at the age of 82 concerned renal autoregulation during hypothermia.<span><sup>5</sup></span></p><p>Gray-haired doctors of today especially remember Mats Wolgast from the Physiology course, perhaps because he always had highly appreciated lectures—educational, instructive, and, to say the least, colorful. Many of his jokes and pranks during lectures are still remembered with great joy, but some of them would probably not survive todays strict woke dogma in the educational system.</p><p>He was also an environmental pioneer, built two environmental houses, and became an acclaimed national celebrity. Soon, busloads of journalists and other stakeholders made the pilgrimage to the family's home in the suburb Sunnersta mainly during weekends and Mats
{"title":"Mats Wolgast (1935–2024)—Obituary","authors":"Bertil Karlmark, Örjan Källskog, Peter Hansell, Mikael Broman, Mats Sjöquist","doi":"10.1111/apha.14235","DOIUrl":"10.1111/apha.14235","url":null,"abstract":"<p>\u0000 \u0000 </p><p>It is with great sadness that we announce to the renal community the passing of Professor emeritus in Physiology Mats Wolgast, Uppsala, Sweden. The closest mourners are the children Charlotta from his marriage to the late Inger Söder Wolgast, and Björn and Åsa from his previous marriage. He died after a period of illness at the age of 89.</p><p>Mats grew up in Bräkne-Hoby, a small town in the county of Blekinge, graduated in Helsingborg and studied medicine in Uppsala. He was instantly hooked on the subject of physiology and remained at the Department of Physiology in Uppsala after his medical studies where he graduated as a PhD in 1968.</p><p>Mats was a genius with the ability to see context and consequences long before the rest of us. The kidney became his main interest and the thesis in 1968 concerned the distribution of blood within the kidney with focus on the medulla with the essence being published in Nature<span><sup>1</sup></span> and Acta Physiologica Scandinavica.<span><sup>2</sup></span> A special room was built at the Biomedical Center for his research with radioactive red blood cells and tailored semiconductor detectors. When the work received a lot of international attention, he became a leading figure in the successful Kidney Research Group whose PhD students were welcomed at many research centers worldwide. He also studied permeability characteristics of charged biological membranes and the interstitial space using complicated mathematical models to explain the gel concept<span><sup>3</sup></span> which probably interfered with the ability to sleep of several referees and journal editors. Some even say he invented his own mathematics. He was also well known for his studies in revealing the dynamics of glomerular filtration.<span><sup>4</sup></span></p><p>Doctors in internal medicine, surgery, radiology, and nephrology approached Mats not only for help but also for collaboration. The need and existence of a sharp theoretical and practical physiologist became the foundation for a large number of clinical dissertations in a variety of fields such as ischemia–reperfusion injury, transplantation, acute kidney injury, and oxidative stress. His last publication at the age of 82 concerned renal autoregulation during hypothermia.<span><sup>5</sup></span></p><p>Gray-haired doctors of today especially remember Mats Wolgast from the Physiology course, perhaps because he always had highly appreciated lectures—educational, instructive, and, to say the least, colorful. Many of his jokes and pranks during lectures are still remembered with great joy, but some of them would probably not survive todays strict woke dogma in the educational system.</p><p>He was also an environmental pioneer, built two environmental houses, and became an acclaimed national celebrity. Soon, busloads of journalists and other stakeholders made the pilgrimage to the family's home in the suburb Sunnersta mainly during weekends and Mats ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379557","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}
Stan F. J. van de Graaf, Coen C. Paulusma, Wietse In het Panhuis
The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient-rich blood enters the liver in the periportal zone and flows through the mid-zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β-catenin, have been shown to play a causal role in the development of metabolic dysfunction-associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport.
{"title":"Getting in the zone: Metabolite transport across liver zones","authors":"Stan F. J. van de Graaf, Coen C. Paulusma, Wietse In het Panhuis","doi":"10.1111/apha.14239","DOIUrl":"10.1111/apha.14239","url":null,"abstract":"<p>The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient-rich blood enters the liver in the periportal zone and flows through the mid-zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β-catenin, have been shown to play a causal role in the development of metabolic dysfunction-associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370295","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}
Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A. Dumesic, Sarah E. Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M. Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio
Aims
Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
Methods
We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
Results
Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
Conclusions
This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.
{"title":"p38α kinase governs muscle strength through PGC1α in mice","authors":"Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A. Dumesic, Sarah E. Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M. Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio","doi":"10.1111/apha.14234","DOIUrl":"10.1111/apha.14234","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted our study using male mice (MCK-cre, p38α<sup>MCK-KO</sup> and PGC1α <sup>MCK-KO</sup>) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>I read with interest the editorial by Bai<span><sup>1</sup></span> on the paper by Yu et al.<span><sup>2</sup></span> on the role of caspase 11 in fever. However, I feel that the author ignores the absolutely critical role that prostaglandin (PG) E<sub>2</sub> production in brain endothelial cells has in generating fever, but rather seems to regard it as an auxiliary mechanism. Although both peripheral and central cytokine production may contribute to fever, as suggested by the study by Yu et al.,<span><sup>2</sup></span> the critical mechanism is PGE<sub>2</sub> synthesis and its binding to EP<sub>3</sub> receptor expressing neurons in the median preoptic nucleus (MnPO) of the hypothalamus.<span><sup>3, 4</sup></span> If PGE<sub>2</sub> synthesis is blocked or EP<sub>3</sub> receptors are deleted in the MnPO, no fever occurs,<span><sup>5, 6</sup></span> even though there still is increased cytokine production in the periphery and in the brain.<span><sup>7</sup></span> The critical PGE<sub>2</sub> synthesis occurs in brain endothelial cells as shown by the absence of fever when the PGE<sub>2</sub> synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1) are deleted from these cells.<span><sup>8</sup></span> Cox-2 and mPGES-1 are in turn induced by cytokine binding to receptors on the endothelial cells<span><sup>9-11</sup></span> (Figure 1). If these receptors, such as those for IL-1 and IL-6, or their downstream signaling molecules are selectively deleted from brain endothelial cells, the fever is suppressed.<span><sup>13-16</sup></span></p><p>It should also be pointed out that the evidence for the involvement of microglial cells in inflammation-induced sickness responses, and in particular in fever, is far from clear. Although it is well recognized that peripheral inflammation activates microglial cells,<span><sup>17</sup></span> the mechanism behind this activation is not fully understood. It is unlikely due to direct action of cytokines on the microglial cells, particularly when it comes to interleukin-1, which is a major pyrogen,<span><sup>18</sup></span> because if transport across the blood–brain barrier at all occurs in any significant amount, microglial cells express negligible levels of IL-1 receptors.<span><sup>19</sup></span> The critical IL-1 receptor-expressing cells for IL-1 activation of microglial cells are the endothelial cells, which via an as-yet-unidentified messenger molecule by a paracrine mechanism activate the microglial cells.<span><sup>20</sup></span></p><p>While it is generally assumed that various sickness symptoms and neuropsychiatric disorders are associated with activated microglia,<span><sup>21</sup></span> apart from a study demonstrating a role of striatal microglial cells in negative affect elicited by peripheral inflammation,<span><sup>22</sup></span> there is very little evidence for a causal relationship between these phenomena. It is not even clear which brain cel
{"title":"Inflammation-induced fever depends on prostaglandin E2 production by brain endothelial cells and EP3 receptors in the median preoptic nucleus of the hypothalamus","authors":"Anders Blomqvist","doi":"10.1111/apha.14238","DOIUrl":"10.1111/apha.14238","url":null,"abstract":"<p>I read with interest the editorial by Bai<span><sup>1</sup></span> on the paper by Yu et al.<span><sup>2</sup></span> on the role of caspase 11 in fever. However, I feel that the author ignores the absolutely critical role that prostaglandin (PG) E<sub>2</sub> production in brain endothelial cells has in generating fever, but rather seems to regard it as an auxiliary mechanism. Although both peripheral and central cytokine production may contribute to fever, as suggested by the study by Yu et al.,<span><sup>2</sup></span> the critical mechanism is PGE<sub>2</sub> synthesis and its binding to EP<sub>3</sub> receptor expressing neurons in the median preoptic nucleus (MnPO) of the hypothalamus.<span><sup>3, 4</sup></span> If PGE<sub>2</sub> synthesis is blocked or EP<sub>3</sub> receptors are deleted in the MnPO, no fever occurs,<span><sup>5, 6</sup></span> even though there still is increased cytokine production in the periphery and in the brain.<span><sup>7</sup></span> The critical PGE<sub>2</sub> synthesis occurs in brain endothelial cells as shown by the absence of fever when the PGE<sub>2</sub> synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1) are deleted from these cells.<span><sup>8</sup></span> Cox-2 and mPGES-1 are in turn induced by cytokine binding to receptors on the endothelial cells<span><sup>9-11</sup></span> (Figure 1). If these receptors, such as those for IL-1 and IL-6, or their downstream signaling molecules are selectively deleted from brain endothelial cells, the fever is suppressed.<span><sup>13-16</sup></span></p><p>It should also be pointed out that the evidence for the involvement of microglial cells in inflammation-induced sickness responses, and in particular in fever, is far from clear. Although it is well recognized that peripheral inflammation activates microglial cells,<span><sup>17</sup></span> the mechanism behind this activation is not fully understood. It is unlikely due to direct action of cytokines on the microglial cells, particularly when it comes to interleukin-1, which is a major pyrogen,<span><sup>18</sup></span> because if transport across the blood–brain barrier at all occurs in any significant amount, microglial cells express negligible levels of IL-1 receptors.<span><sup>19</sup></span> The critical IL-1 receptor-expressing cells for IL-1 activation of microglial cells are the endothelial cells, which via an as-yet-unidentified messenger molecule by a paracrine mechanism activate the microglial cells.<span><sup>20</sup></span></p><p>While it is generally assumed that various sickness symptoms and neuropsychiatric disorders are associated with activated microglia,<span><sup>21</sup></span> apart from a study demonstrating a role of striatal microglial cells in negative affect elicited by peripheral inflammation,<span><sup>22</sup></span> there is very little evidence for a causal relationship between these phenomena. It is not even clear which brain cel","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337538","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}
Xueyu Han, Shengnan Xu, Ke Hu, Yi Yu, Xiukun Wang, Chuan Qu, Bo Yang, Xin Liu
Aim
Vascular smooth muscle cell (VSMC) phenotypic switching has been reported to regulate vascular function and thoracic aortic aneurysm and dissection (TAAD) progression. Early growth response 1 (Egr1) is associated with the differentiation of VSMCs. However, the mechanisms through which Egr1 participates in the regulation of VSMCs and progression of TAAD remain unknown. This study aimed to investigate the role of Egr1 in the phenotypic switching of VSMCs and the development of TAAD.
Methods
Wild-type C57BL/6 and SMC-specific Egr1-knockout mice were used as experimental subjects and fed β-aminopropionitrile for 4 weeks to construct the TAAD model. Ultrasound and aortic staining were performed to examine the pathological features in thoracic aortic tissues. Transwell, wound healing, CCK8, and immunofluorescence assays detected the migration and proliferation of synthetic VSMCs. Egr1 was directly bound to the promoter of Krüppel-like factor 5 (KLF5) and promoted the expression of KLF5, which was validated by JASPAR database and dual-luciferase reporter assay.
Results
Egr1 expression increased and was partially co-located with VSMCs in aortic tissues of mice with TAAD. SMC-specific Egr1 deficiency alleviated TAAD and inhibited the phenotypic switching of VSMC. Egr1 knockdown prevented the phenotypic switching of VSMCs and subsequently suppressed the migration and proliferation of synthetic VSMCs. The inhibitory effects of Egr1 deficiency on VSMCs were blunted once KLF5 was overexpressed.
Conclusion
Egr1 aggravated the development of TAAD by promoting the phenotypic switching of VSMCs via enhancing the transcriptional activation of KLF5. These results suggest that inhibition of SMC-specific Egr1 expression is a promising therapy for TAAD.
{"title":"Early growth response 1 exacerbates thoracic aortic aneurysm and dissection of mice by inducing the phenotypic switching of vascular smooth muscle cell through the activation of Krüppel-like factor 5","authors":"Xueyu Han, Shengnan Xu, Ke Hu, Yi Yu, Xiukun Wang, Chuan Qu, Bo Yang, Xin Liu","doi":"10.1111/apha.14237","DOIUrl":"10.1111/apha.14237","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Vascular smooth muscle cell (VSMC) phenotypic switching has been reported to regulate vascular function and thoracic aortic aneurysm and dissection (TAAD) progression. Early growth response 1 (Egr1) is associated with the differentiation of VSMCs. However, the mechanisms through which Egr1 participates in the regulation of VSMCs and progression of TAAD remain unknown. This study aimed to investigate the role of Egr1 in the phenotypic switching of VSMCs and the development of TAAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Wild-type C57BL/6 and SMC-specific Egr1-knockout mice were used as experimental subjects and fed β-aminopropionitrile for 4 weeks to construct the TAAD model. Ultrasound and aortic staining were performed to examine the pathological features in thoracic aortic tissues. Transwell, wound healing, CCK8, and immunofluorescence assays detected the migration and proliferation of synthetic VSMCs. Egr1 was directly bound to the promoter of Krüppel-like factor 5 (KLF5) and promoted the expression of KLF5, which was validated by JASPAR database and dual-luciferase reporter assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Egr1 expression increased and was partially co-located with VSMCs in aortic tissues of mice with TAAD. SMC-specific Egr1 deficiency alleviated TAAD and inhibited the phenotypic switching of VSMC. Egr1 knockdown prevented the phenotypic switching of VSMCs and subsequently suppressed the migration and proliferation of synthetic VSMCs. The inhibitory effects of Egr1 deficiency on VSMCs were blunted once KLF5 was overexpressed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Egr1 aggravated the development of TAAD by promoting the phenotypic switching of VSMCs via enhancing the transcriptional activation of KLF5. These results suggest that inhibition of SMC-specific Egr1 expression is a promising therapy for TAAD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337537","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}
Pa Reum Lee, Taewoong Ha, Hoon-Seong Choi, Seung Eun Lee, Chungho Kim, Gyu-Sang Hong
Aim
This investigation addresses Piezo1's expression and mechanistic role in dorsal root ganglion (DRG) neurons and delineates its participation in mechanical and inflammatory pain modulation.
Methods
We analyzed Piezo1's expression patterns in DRG neurons and utilized Piezo1-specific shRNA to modulate its activity. Electrophysiological assessments of mechanically activated (MA) currents in DRG neurons and behavioral analyses in mouse models of inflammatory pain were conducted to elucidate Piezo1's functional implications. Additionally, we investigated the excitability of TRPV1-expressing DRG neurons, particularly under inflammatory conditions.
Results
Piezo1 was preferentially expressed in DRG neurons co-expressing the TRPV1 nociceptor marker. Knockdown of Piezo1 attenuated intermediately adapting MA currents and lessened tactile pain hypersensitivity in models of inflammatory pain. Additionally, silencing Piezo1 modified the excitability of TRPV1-expressing neurons under inflammatory stress.
Conclusion
Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain, indicating its potential as a novel target for pain management therapies. Our finding not only advances the understanding of nociceptive signaling but also emphasizes the therapeutic potential of modulating Piezo1 in the treatment of pain.
{"title":"Piezo1 mediates mechanical signals in TRPV1-positive nociceptors in mice","authors":"Pa Reum Lee, Taewoong Ha, Hoon-Seong Choi, Seung Eun Lee, Chungho Kim, Gyu-Sang Hong","doi":"10.1111/apha.14236","DOIUrl":"10.1111/apha.14236","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This investigation addresses Piezo1's expression and mechanistic role in dorsal root ganglion (DRG) neurons and delineates its participation in mechanical and inflammatory pain modulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed Piezo1's expression patterns in DRG neurons and utilized Piezo1-specific shRNA to modulate its activity. Electrophysiological assessments of mechanically activated (MA) currents in DRG neurons and behavioral analyses in mouse models of inflammatory pain were conducted to elucidate Piezo1's functional implications. Additionally, we investigated the excitability of TRPV1-expressing DRG neurons, particularly under inflammatory conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Piezo1 was preferentially expressed in DRG neurons co-expressing the TRPV1 nociceptor marker. Knockdown of Piezo1 attenuated intermediately adapting MA currents and lessened tactile pain hypersensitivity in models of inflammatory pain. Additionally, silencing Piezo1 modified the excitability of TRPV1-expressing neurons under inflammatory stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain, indicating its potential as a novel target for pain management therapies. Our finding not only advances the understanding of nociceptive signaling but also emphasizes the therapeutic potential of modulating Piezo1 in the treatment of pain.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337539","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}
Renal excretion of excess HCO3− depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO3− excretion following oral NaHCO3-loading may be a simple in vivo biomarker of CFTR function. In this study, we investigated changes in urine acid/base parameters following oral NaHCO3-loading to comprehensively assess the physiological response to the test and evaluate HCO3− as the primary test result.
Methods
Urine acid/base parameters (titratable acid (TA), NH4+, net acid excretion (NAE) and pH) were measured in bio-banked urine samples from controls (n = 10) and pwCF (n = 50) who completed the challenged urine HCO3− test. The association between urine acid/base excretion parameters and clinical CF disease characteristics and CFTR modulator therapy-induced changes were assessed.
Results
Before treatment, challenged urine acid/base excretion associated with important CF disease characteristics. TA excretion and NAE were lower in pwCF with residual function mutations, 7.9 and 16.6 mmol/3 h, respectively, and lower TA excretion and NAE associated with pancreatic sufficiency. A lower excretion of TA, NH4+, and NAE associated with a higher percentage of predicted FEV1 (1.3%, 2.5% and 0.8% per mmol/3 h higher, respectively). Modulator treatment decreased TA excretion and NAE (−2.9 and −5.3 mmol/3 h, respectively).
Conclusion
Following acute NaHCO3-loading, increased base excretion is mirrored by decreased acid excretion. Urine HCO3− excretion sufficiently represents the additional urine acid/base parameters as test result. The observed changes in acid excretion support CFTR modulator-induced increase of CFTR-dependent type B intercalated cell HCO3− secretion and the use of the challenged urine HCO3− test as a possible CFTR-biomarker.
{"title":"The challenged urine bicarbonate excretion test in cystic fibrosis: A comprehensive analysis of urine acid/base parameters","authors":"Amalie Q. Rousing, Majbritt Jeppesen, Søren Jensen-Fangel, Jens Leipziger, Mads V. Sorensen, Peder Berg","doi":"10.1111/apha.14233","DOIUrl":"10.1111/apha.14233","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Renal excretion of excess HCO<sub>3</sub><sup>−</sup> depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO<sub>3</sub><sup>−</sup> excretion following oral NaHCO<sub>3</sub>-loading may be a simple in vivo biomarker of CFTR function. In this study, we investigated changes in urine acid/base parameters following oral NaHCO<sub>3</sub>-loading to comprehensively assess the physiological response to the test and evaluate HCO<sub>3</sub><sup>−</sup> as the primary test result.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Urine acid/base parameters (titratable acid (TA), NH<sub>4</sub><sup>+</sup>, net acid excretion (NAE) and pH) were measured in bio-banked urine samples from controls (<i>n</i> = 10) and pwCF (<i>n</i> = 50) who completed the challenged urine HCO<sub>3</sub><sup>−</sup> test. The association between urine acid/base excretion parameters and clinical CF disease characteristics and CFTR modulator therapy-induced changes were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Before treatment, challenged urine acid/base excretion associated with important CF disease characteristics. TA excretion and NAE were lower in pwCF with residual function mutations, 7.9 and 16.6 mmol/3 h, respectively, and lower TA excretion and NAE associated with pancreatic sufficiency. A lower excretion of TA, NH<sub>4</sub><sup>+</sup>, and NAE associated with a higher percentage of predicted FEV<sub>1</sub> (1.3%, 2.5% and 0.8% per mmol/3 h higher, respectively). Modulator treatment decreased TA excretion and NAE (−2.9 and −5.3 mmol/3 h, respectively).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Following acute NaHCO<sub>3</sub>-loading, increased base excretion is mirrored by decreased acid excretion. Urine HCO<sub>3</sub><sup>−</sup> excretion sufficiently represents the additional urine acid/base parameters as test result. The observed changes in acid excretion support CFTR modulator-induced increase of CFTR-dependent type B intercalated cell HCO<sub>3</sub><sup>−</sup> secretion and the use of the challenged urine HCO<sub>3</sub><sup>−</sup> test as a possible CFTR-biomarker.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277440","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}
Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini
AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (−/−) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3−/− mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.
{"title":"Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet‐induced obesity","authors":"Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini","doi":"10.1111/apha.14232","DOIUrl":"https://doi.org/10.1111/apha.14232","url":null,"abstract":"AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (<jats:sup>−/−</jats:sup>) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3<jats:sup>−/−</jats:sup> mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"32 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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