Pub Date : 2024-11-04DOI: 10.1016/j.bbi.2024.11.009
Stella Liong
{"title":"Detecting the early warning signs of neonatal brain injury","authors":"Stella Liong","doi":"10.1016/j.bbi.2024.11.009","DOIUrl":"10.1016/j.bbi.2024.11.009","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 948-949"},"PeriodicalIF":8.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589775","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}
Pub Date : 2024-11-04DOI: 10.1016/j.bbi.2024.11.002
Xiaolin Li , Xinxia Zhu , Parham Diba , Xuan Shi , Frank Vrieling , Fleur A.C. Jansen , Michiel G.J. Balvers , Ian de Bus , Peter R. Levasseur , Ariana Sattler , Paige C. Arneson-Wissink , Mieke Poland , Renger F. Witkamp , Klaske van Norren , Daniel L. Marks
Hypothalamic inflammation often coincides with cancer and cachexia-anorexia. Prior work established the significance of tumor-derived inflammatory factors in triggering hypothalamic inflammation, yet the precise mechanisms remained elusive. Here, we demonstrate that prostaglandin E2 (PGE2), produced in the tumor via cyclooxygenase-2 (COX-2), plays a pivotal role in this context. PGE2 itself directly exerts pro-inflammatory effects on the hypothalamus through the EP4 receptor, while also augmenting hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived pathogen-associated molecular patterns (PAMPs). In tumor-bearing mice, we confirm this synergistic interaction between tumor-derived COX-2/PGE2 and host-derived lipopolysaccharide (LPS) in amplifying hypothalamic inflammation. Supporting this mechanism we find that the tumor-specific knockout of COX-2 attenuates hypothalamic inflammation and improves survival in mice. Together, these findings highlight the mechanisms of tumor-associated COX-2 in fuelling hypothalamic inflammation. They also emphasize the potential of tumor-specific COX-2 inhibition and targeting gut permeability as a novel therapeutic strategy for improving clinical outcomes in cancer patients.
{"title":"Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation","authors":"Xiaolin Li , Xinxia Zhu , Parham Diba , Xuan Shi , Frank Vrieling , Fleur A.C. Jansen , Michiel G.J. Balvers , Ian de Bus , Peter R. Levasseur , Ariana Sattler , Paige C. Arneson-Wissink , Mieke Poland , Renger F. Witkamp , Klaske van Norren , Daniel L. Marks","doi":"10.1016/j.bbi.2024.11.002","DOIUrl":"10.1016/j.bbi.2024.11.002","url":null,"abstract":"<div><div>Hypothalamic inflammation often coincides with cancer and cachexia-anorexia. Prior work established the significance of tumor-derived inflammatory factors in triggering hypothalamic inflammation, yet the precise mechanisms remained elusive. Here, we demonstrate that prostaglandin E2 (PGE2), produced in the tumor via cyclooxygenase-2 (COX-2), plays a pivotal role in this context. PGE2 itself directly exerts pro-inflammatory effects on the hypothalamus through the EP4 receptor, while also augmenting hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived pathogen-associated molecular patterns (PAMPs). In tumor-bearing mice, we confirm this synergistic interaction between tumor-derived COX-2/PGE2 and host-derived lipopolysaccharide (LPS) in amplifying hypothalamic inflammation. Supporting this mechanism we find that the tumor-specific knockout of COX-2 attenuates hypothalamic inflammation and improves survival in mice. Together, these findings highlight the mechanisms of tumor-associated COX-2 in fuelling hypothalamic inflammation. They also emphasize the potential of tumor-specific COX-2 inhibition and targeting gut permeability as a novel therapeutic strategy for improving clinical outcomes in cancer patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 886-902"},"PeriodicalIF":8.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589780","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 : 2024-11-03DOI: 10.1016/j.bbi.2024.11.004
David Walzik , Niklas Joisten , Alexander Schenk , Sina Trebing , Kirill Schaaf , Alan J Metcalfe , Polyxeni Spiliopoulou , Johanna Hiefner , Adrian McCann , Carsten Watzl , Per Magne Ueland , Sebastian Gehlert , Anna Worthmann , Charles Brenner , Philipp Zimmer
Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central electron carriers in biological energy metabolism. Low NAD+ levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD+ levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD+ levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD+ metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD+ metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that – similar to skeletal muscle – NAD+ salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+ salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD+ levels and reduced serum levels of the NAD+ precursor nicotinamide. These results demonstrate that acute exercise triggers NAD+ biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.
{"title":"Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells","authors":"David Walzik , Niklas Joisten , Alexander Schenk , Sina Trebing , Kirill Schaaf , Alan J Metcalfe , Polyxeni Spiliopoulou , Johanna Hiefner , Adrian McCann , Carsten Watzl , Per Magne Ueland , Sebastian Gehlert , Anna Worthmann , Charles Brenner , Philipp Zimmer","doi":"10.1016/j.bbi.2024.11.004","DOIUrl":"10.1016/j.bbi.2024.11.004","url":null,"abstract":"<div><div>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) coenzymes are the central electron carriers in biological energy metabolism. Low NAD<sup>+</sup> levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD<sup>+</sup> levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD<sup>+</sup> levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD<sup>+</sup> metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD<sup>+</sup> metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that – similar to skeletal muscle – NAD<sup>+</sup> salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD<sup>+</sup> salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD<sup>+</sup> levels and reduced serum levels of the NAD<sup>+</sup> precursor nicotinamide. These results demonstrate that acute exercise triggers NAD<sup>+</sup> biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1011-1023"},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581888","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 : 2024-11-03DOI: 10.1016/j.bbi.2024.11.006
Zinovia Maridaki , Georgios Syrros , Stella Gianna Delichatsiou , Jerry Warsh , Gerasimos N. Konstantinou
Background
Recent research has underscored the critical role of blood–brain barrier (BBB) integrity in psychiatric disorders, highlighting disruptions in tight junction (TJ) proteins, specifically claudin-5 and occludin. These proteins are pivotal in maintaining the BBB’s selective permeability, which is essential for brain homeostasis. Altered levels of the TJ proteins have been observed in various psychiatric conditions, suggesting potential as biomarkers for the pathophysiology of these disorders. This systematic review synthesizes existing research on the alterations of claudin-5 and occludin levels in the serum of individuals with psychiatric disorders, evaluating their correlation with BBB dysfunction and psychiatric pathophysiology.
Methods
In adherence to the PRISMA guidelines, a comprehensive search strategy was employed, utilizing databases such as PubMed, Google Scholar, Web of Science, and Scopus. The review encompassed studies published between 2000 and 2024 that measured serum claudin-5 and occludin levels of psychiatric patients. Thorough data extraction and synthesis were conducted.
Results
Seventeen studies met the inclusion criteria. Key findings include indications for increased claudin-5 levels in Schizophrenia, Bipolar Disorder, Depression, and Specific learning disorder, and increased occludin levels in ADHD and Autism Spectrum Disorder patients. No significant differences were found in studies of patients with Alcohol Use and Insomnia Disorder.
Conclusions
The review underscores the potential association between altered serum levels of claudin-5 and occludin and psychiatric disorders, supporting their utility as biomarkers for BBB integrity and psychiatric pathophysiology. Further research is essential to elucidate the mechanisms linking TJ protein alterations with pathophysiology and, potentially, neuroprogression in psychiatric disorders, which could lead to novel diagnostic and therapeutic strategies.
{"title":"Claudin-5 and occludin levels in patients with psychiatric disorders − A systematic review","authors":"Zinovia Maridaki , Georgios Syrros , Stella Gianna Delichatsiou , Jerry Warsh , Gerasimos N. Konstantinou","doi":"10.1016/j.bbi.2024.11.006","DOIUrl":"10.1016/j.bbi.2024.11.006","url":null,"abstract":"<div><h3>Background</h3><div>Recent research has underscored the critical role of blood–brain barrier (BBB) integrity in psychiatric disorders, highlighting disruptions in tight junction (TJ) proteins, specifically claudin-5 and occludin. These proteins are pivotal in maintaining the BBB’s selective permeability, which is essential for<!--> <!-->brain homeostasis. Altered levels of the TJ proteins have been observed in various psychiatric conditions, suggesting potential as biomarkers for the pathophysiology of these disorders. This systematic review synthesizes existing research on the alterations of claudin-5 and occludin levels in the serum of individuals with psychiatric disorders, evaluating their correlation with BBB dysfunction and psychiatric pathophysiology.</div></div><div><h3>Methods</h3><div>In adherence to the PRISMA guidelines, a comprehensive search strategy was employed, utilizing databases such as PubMed, Google Scholar, Web of Science, and Scopus. The review encompassed studies published between 2000 and 2024 that measured serum claudin-5 and occludin levels of psychiatric patients. Thorough data extraction and synthesis were conducted.</div></div><div><h3>Results</h3><div>Seventeen studies met the inclusion criteria. Key findings include indications for increased claudin-5 levels in Schizophrenia, Bipolar Disorder, Depression, and Specific learning disorder, and increased occludin levels in ADHD and Autism Spectrum Disorder patients. No significant differences were found in studies of patients with Alcohol Use and Insomnia Disorder.</div></div><div><h3>Conclusions</h3><div>The review underscores the potential association between altered serum levels of claudin-5 and occludin and psychiatric disorders, supporting their utility as biomarkers for BBB integrity and psychiatric pathophysiology. Further research is essential to elucidate the mechanisms linking TJ protein alterations with pathophysiology and, potentially, neuroprogression in psychiatric disorders, which could lead to novel diagnostic and therapeutic strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 865-875"},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581969","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}
Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca2+ concentration and subsequent enhancement of Ca2+ influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain.
{"title":"Fibroblast-derived IL-33 exacerbates orofacial neuropathic pain via the activation of TRPA1 in trigeminal ganglion neurons","authors":"Yousuke Ikehata , Eri Oshima , Yoshinori Hayashi , Yukinori Tanaka , Hitoshi Sato , Suzuro Hitomi , Miho Shiratori-Hayashi , Kentaro Urata , Yuki Kimura , Ikuko Shibuta , Seigo Ohba , Koichi Iwata , Kentaro Mizuta , Tatsuo Shirota , Masamichi Shinoda","doi":"10.1016/j.bbi.2024.11.003","DOIUrl":"10.1016/j.bbi.2024.11.003","url":null,"abstract":"<div><div>Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca<sup>2+</sup> concentration and subsequent enhancement of Ca<sup>2+</sup> influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 982-996"},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581978","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}
Pub Date : 2024-11-03DOI: 10.1016/j.bbi.2024.11.007
J. Douglas Bremner , Scott J. Russo , Richard Gallagher , Naomi M. Simon
Background
COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome.
Methods
This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression.
Results
Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas.
Conclusions
Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.
{"title":"Acute and long-term effects of COVID-19 on brain and mental health: A narrative review","authors":"J. Douglas Bremner , Scott J. Russo , Richard Gallagher , Naomi M. Simon","doi":"10.1016/j.bbi.2024.11.007","DOIUrl":"10.1016/j.bbi.2024.11.007","url":null,"abstract":"<div><h3>Background</h3><div>COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome.</div></div><div><h3>Methods</h3><div>This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression.</div></div><div><h3>Results</h3><div>Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas.</div></div><div><h3>Conclusions</h3><div>Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 928-945"},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581858","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}
Pub Date : 2024-11-03DOI: 10.1016/j.bbi.2024.10.036
Marie Louise Bønnelykke-Behrndtz , Mathias Clasen , Josephine N.E. Benckendorff , Karoline Assifuah Kristjansen , Linea Høyer , Camilla Mensel , Kumanan Nanthan , Marc M. Andersen
<div><div>A fear reaction is fundamental for survival and naturally activates the adrenergic system, prompting an acute and vital flight-or-fight response. While sustained stress is associated with unhealthy low-grade inflammation, more acute and transient activation of the adrenergic system has been suggested to impact the immune system and subsequently attenuate low-grade inflammation, e.g. through cold exposure or hyperventilation. Voluntary exposure to frightening stimuli, such as scary entertainment, is another reliable activator of the adrenergic system, yet its impact on the immune system and low-grade inflammation is unknown.</div><div>The objectives of this study are to i. assess proportional changes of participants with low-grade inflammation at and three days after a voluntary frightening event, and ii. explore mean value alterations in inflammatory markers and immune cells over time.</div><div>We recruited adult participants among visitors to a real-life intense frightening haunted house attraction, located in Vejle, Denmark. The overall fright potential of the exposure was estimated through heart rate (HR) monitoring and self-reported levels of fear. Low-grade inflammation (defined as high sensitive C-reactive protein (hs-CRP) > 3 mg/L)) and immune cells (subtypes of leukocytes) were measured from blood samples immediately before, immediately after, and three days after the haunted house event.</div><div>A total of 113 participants, 69 females (61.1 %), and 44 males (38.9 %), with a mean age of 29.7 (SD 10.1) were included in the analyses. The average duration of exposure was 50 min and 51 s, while the mean HR throughout the event was 111.1 BPM (mean SD 10.1), and the mean subjective reported scare level was 5.4 (SD 1.9) on a Likert scale ranging from 1 to 9. Twenty-two participants exhibited low-grade inflammation (hs-CRP > 3 mg/L) at the event, with 10 participants normalizing their hs-CRP levels three days post-event. Seven participants had normal hs-CRP levels at the event, but low-grade inflammation three days post-event. Thus, we found no proportional difference between participants with low-grade inflammation at the event (19.5 %) and three days after the event (16.8 %) (diff. −2.7 %; 95 % CI: −10.7 to 5.4, p = 0.47). For the 22 participants exhibiting low-grade inflammation at the event, 18 participants (82 %) decreased their hs-CRP levels, with a mean decrease in hs-CRP from 5.7 mg/L pre-event to 3.7 mg/L three days post-event (diff. −2.0, 95 % CI: −3.2 to −0.7, p = 0.003). Supporting an overall attenuation of inflammation, total leukocytes and lymphocytes decreased for both participants with low-grade inflammation and with normal inflammatory levels, when comparing levels pre- and three days post-event, although all mean levels remained within the normal range.</div><div>Conclusively, we find no proportional differences in participants exhibiting low-grade inflammation (hs-CRP > 3) when comparing levels at and thre
{"title":"Unraveling the effect of recreational fear on inflammation: A prospective cohort field study","authors":"Marie Louise Bønnelykke-Behrndtz , Mathias Clasen , Josephine N.E. Benckendorff , Karoline Assifuah Kristjansen , Linea Høyer , Camilla Mensel , Kumanan Nanthan , Marc M. Andersen","doi":"10.1016/j.bbi.2024.10.036","DOIUrl":"10.1016/j.bbi.2024.10.036","url":null,"abstract":"<div><div>A fear reaction is fundamental for survival and naturally activates the adrenergic system, prompting an acute and vital flight-or-fight response. While sustained stress is associated with unhealthy low-grade inflammation, more acute and transient activation of the adrenergic system has been suggested to impact the immune system and subsequently attenuate low-grade inflammation, e.g. through cold exposure or hyperventilation. Voluntary exposure to frightening stimuli, such as scary entertainment, is another reliable activator of the adrenergic system, yet its impact on the immune system and low-grade inflammation is unknown.</div><div>The objectives of this study are to i. assess proportional changes of participants with low-grade inflammation at and three days after a voluntary frightening event, and ii. explore mean value alterations in inflammatory markers and immune cells over time.</div><div>We recruited adult participants among visitors to a real-life intense frightening haunted house attraction, located in Vejle, Denmark. The overall fright potential of the exposure was estimated through heart rate (HR) monitoring and self-reported levels of fear. Low-grade inflammation (defined as high sensitive C-reactive protein (hs-CRP) > 3 mg/L)) and immune cells (subtypes of leukocytes) were measured from blood samples immediately before, immediately after, and three days after the haunted house event.</div><div>A total of 113 participants, 69 females (61.1 %), and 44 males (38.9 %), with a mean age of 29.7 (SD 10.1) were included in the analyses. The average duration of exposure was 50 min and 51 s, while the mean HR throughout the event was 111.1 BPM (mean SD 10.1), and the mean subjective reported scare level was 5.4 (SD 1.9) on a Likert scale ranging from 1 to 9. Twenty-two participants exhibited low-grade inflammation (hs-CRP > 3 mg/L) at the event, with 10 participants normalizing their hs-CRP levels three days post-event. Seven participants had normal hs-CRP levels at the event, but low-grade inflammation three days post-event. Thus, we found no proportional difference between participants with low-grade inflammation at the event (19.5 %) and three days after the event (16.8 %) (diff. −2.7 %; 95 % CI: −10.7 to 5.4, p = 0.47). For the 22 participants exhibiting low-grade inflammation at the event, 18 participants (82 %) decreased their hs-CRP levels, with a mean decrease in hs-CRP from 5.7 mg/L pre-event to 3.7 mg/L three days post-event (diff. −2.0, 95 % CI: −3.2 to −0.7, p = 0.003). Supporting an overall attenuation of inflammation, total leukocytes and lymphocytes decreased for both participants with low-grade inflammation and with normal inflammatory levels, when comparing levels pre- and three days post-event, although all mean levels remained within the normal range.</div><div>Conclusively, we find no proportional differences in participants exhibiting low-grade inflammation (hs-CRP > 3) when comparing levels at and thre","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1042-1051"},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581938","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 : 2024-11-03DOI: 10.1016/j.bbi.2024.11.008
Alice Buonfiglioli, Raphael Kübler, Roy Missall, Renske De Jong, Stephanie Chan, Verena Haage, Stefan Wendt, Ada J Lin, Daniele Mattei, Mara Graziani, Brooke Latour, Frederieke Gigase, Rebecca Chiu, Ya Zhang, Haakon B Nygaard, Philip L De Jager, Lot D De Witte
Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
{"title":"A microglia-containing cerebral organoid model to study early life immune challenges.","authors":"Alice Buonfiglioli, Raphael Kübler, Roy Missall, Renske De Jong, Stephanie Chan, Verena Haage, Stefan Wendt, Ada J Lin, Daniele Mattei, Mara Graziani, Brooke Latour, Frederieke Gigase, Rebecca Chiu, Ya Zhang, Haakon B Nygaard, Philip L De Jager, Lot D De Witte","doi":"10.1016/j.bbi.2024.11.008","DOIUrl":"10.1016/j.bbi.2024.11.008","url":null,"abstract":"<p><p>Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581765","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}
Pub Date : 2024-11-02DOI: 10.1016/j.bbi.2024.10.029
Ying Chen , John Man-Tak Chu , Jia-Xin Liu , Yu-Juan Duan , Zheng-Kai Liang , Xin Zou , Ming Wei , Wen-Jun Xin , Ting Xu , Gordon Tin-Chun Wong , Xia Feng
CD3(+) CD4(−) CD8(−) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulates complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.
{"title":"Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice","authors":"Ying Chen , John Man-Tak Chu , Jia-Xin Liu , Yu-Juan Duan , Zheng-Kai Liang , Xin Zou , Ming Wei , Wen-Jun Xin , Ting Xu , Gordon Tin-Chun Wong , Xia Feng","doi":"10.1016/j.bbi.2024.10.029","DOIUrl":"10.1016/j.bbi.2024.10.029","url":null,"abstract":"<div><div>CD3(+) CD4(−) CD8(−) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulates complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 965-981"},"PeriodicalIF":8.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567252","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}
Pub Date : 2024-11-01DOI: 10.1016/j.bbi.2024.10.031
Igor Rafael Correia Rocha , Maggie R. Finch , Jayson B. Ball , Michael E. Harland , Madison Clements , Suzanne Green-Fulgham , Guiyun Song , Yi Liu , Daniel Banov , Linda R. Watkins
Psoriasis is a chronic immune-mediated skin disorder characterized by intense local inflammation, epidermal hyperplasia, and leukocyte infiltration. Current treatment approaches for psoriasis aim to alleviate symptoms and prevent disease progression, including systemically administered drugs with whole body side effects. Despite some advances in psoriasis treatment, success has been quite limited. To begin to address this challenge, we undertook an initial investigation of whether transcutaneous delivery of an endogenous anti-inflammatory cytokine could provide an effective, local treatment of psoriatic-like skin conditions. To do this, we utilized a previously documented rodent model of psoriasis, induced via a single topical application of Imiquimod (IMQ) to the shaved back of rats. The therapeutic approach used for this initial investigation was delivery of plasmid DNA encoding rat interleukin-10 (pDNA-rIL10), a non-viral gene therapy approach previously shown to be effective in suppressing neuroinflammatory disorders after localized delivery either intracerebrally or intrathecally. Translation of this CNS therapeutic for use in psoriatic-like skin disorders required reformulation to enable transcutaneous delivery. Toward that end, pDNA-rIL10 was topically applied in Lipoderm HMW, a base explicitly designed to deliver higher molecular weight compounds into skin. Here we show that a single topical application of pDNA-rIL10 in Lipoderm HMW was effective in decreasing mRNA levels of pro-inflammatory cytokines as well as reducing the recruitment of T-cells to IMQ-treated skin. Furthermore, this transcutaneous IL-10 gene therapy decreased signs of skin inflammation, reflected by reduced erythema. Moreover, the results provide an initial indication that IL10 may stimulate hair regrowth in psoriatic-like skin.
银屑病是一种由免疫介导的慢性皮肤病，以局部强烈发炎、表皮增生和白细胞浸润为特征。目前治疗银屑病的方法旨在缓解症状和防止病情恶化，包括全身用药，但副作用较大。尽管银屑病治疗取得了一些进展，但取得的成功仍然十分有限。为了开始应对这一挑战，我们对经皮给药内源性抗炎细胞因子能否有效治疗银屑病样皮肤病进行了初步研究。为此，我们利用了以前记录的啮齿动物银屑病模型，通过在剃光毛发的大鼠背部单次局部应用咪喹莫特（IMQ）来诱导银屑病。这项初步研究采用的治疗方法是递送编码大鼠白细胞介素-10（pDNA-rIL10）的 DNA 质粒，这种非病毒基因治疗方法以前曾被证明在脑内或经皮内局部递送后能有效抑制神经炎性疾病。要将这种中枢神经系统疗法应用于银屑病样皮肤病，需要重新配制，以实现经皮给药。为此，pDNA-rIL10 在 Lipoderm HMW（一种专门用于向皮肤输送高分子量化合物的基质）中进行了局部应用。我们在这里展示了在 Lipoderm HMW 中局部施用 pDNA-rIL10 能有效降低促炎细胞因子的 mRNA 水平，并减少 T 细胞对 IMQ 处理过的皮肤的招募。此外，这种经皮 IL-10 基因疗法还能减少皮肤炎症症状，红斑的减少就反映了这一点。此外，研究结果还初步表明，IL10 可刺激银屑病样皮肤的毛发再生。
{"title":"An initial investigation of transcutaneous delivery of plasmid DNA encoding interleukin-10 for the treatment of psoriatic skin conditions","authors":"Igor Rafael Correia Rocha , Maggie R. Finch , Jayson B. Ball , Michael E. Harland , Madison Clements , Suzanne Green-Fulgham , Guiyun Song , Yi Liu , Daniel Banov , Linda R. Watkins","doi":"10.1016/j.bbi.2024.10.031","DOIUrl":"10.1016/j.bbi.2024.10.031","url":null,"abstract":"<div><div>Psoriasis is a chronic immune-mediated skin disorder characterized by intense local inflammation, epidermal hyperplasia, and leukocyte infiltration. Current treatment approaches for psoriasis aim to alleviate symptoms and prevent disease progression, including systemically administered drugs with whole body side effects. Despite some advances in psoriasis treatment, success has been quite limited. To begin to address this challenge, we undertook an initial investigation of whether transcutaneous delivery of an endogenous anti-inflammatory cytokine could provide an effective, local treatment of psoriatic-like skin conditions. To do this, we utilized a previously documented rodent model of psoriasis, induced via a single topical application of Imiquimod (IMQ) to the shaved back of rats. The therapeutic approach used for this initial investigation was delivery of plasmid DNA encoding rat interleukin-10 (pDNA-rIL10), a non-viral gene therapy approach previously shown to be effective in suppressing neuroinflammatory disorders after localized delivery either intracerebrally or intrathecally. Translation of this CNS therapeutic for use in psoriatic-like skin disorders required reformulation to enable transcutaneous delivery. Toward that end, pDNA-rIL10 was topically applied in Lipoderm HMW, a base explicitly designed to deliver higher molecular weight compounds into skin. Here we show that a single topical application of pDNA-rIL10 in Lipoderm HMW was effective in decreasing mRNA levels of pro-inflammatory cytokines as well as reducing the recruitment of T-cells to IMQ-treated skin. Furthermore, this transcutaneous IL-10 gene therapy decreased signs of skin inflammation, reflected by reduced erythema. Moreover, the results provide an initial indication that IL10 may stimulate hair regrowth in psoriatic-like skin.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 903-913"},"PeriodicalIF":8.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567249","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号