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
{"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}
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
{"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}
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
{"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}
{"title":"Evaluating Methodological validity in the Analysis of Tai Chi and cognitive behavioral therapy for inflammation Reduction in Insomnia: A Letter to the Editor","authors":"Akiko Eto-Kimura , Shunsuke Yasuo , Yuki Kataoka","doi":"10.1016/j.bbi.2024.10.037","DOIUrl":"10.1016/j.bbi.2024.10.037","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 863-864"},"PeriodicalIF":8.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557204","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}
{"title":"In response to Eto-Kimura et al","authors":"","doi":"10.1016/j.bbi.2024.10.038","DOIUrl":"10.1016/j.bbi.2024.10.038","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1024-1025"},"PeriodicalIF":8.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563804","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}
{"title":"Serology and Alzheimer’s disease: Is infectious disease in the driver’s seat?","authors":"A.L. Dawson , A.A. Willette","doi":"10.1016/j.bbi.2024.10.035","DOIUrl":"10.1016/j.bbi.2024.10.035","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 946-947"},"PeriodicalIF":8.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557206","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}
Urvinder Kaur Sardarni , Anoop T Ambikan , Arpan Acharya , Samuel D Johnson , Sean N. Avedissian , Ákos Végvári , Ujjwal Neogi , Siddappa N. Byrareddy
{"title":"SARS-CoV-2 variants mediated tissue-specific metabolic reprogramming determines the disease pathophysiology in a hamster model","authors":"Urvinder Kaur Sardarni , Anoop T Ambikan , Arpan Acharya , Samuel D Johnson , Sean N. Avedissian , Ákos Végvári , Ujjwal Neogi , Siddappa N. Byrareddy","doi":"10.1016/j.bbi.2024.10.032","DOIUrl":"10.1016/j.bbi.2024.10.032","url":null,"abstract":"<div><div>Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus<!--> <!-->2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between tissues and SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed the presence of increased SARS-CoV-2 genomic RNA in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 914-927"},"PeriodicalIF":8.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557205","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}
Rhonda L. McFleder , Thomas Musacchio , Johanna Keller , Susanne Knorr , Tobias Petschner , Jia Zhi Chen , Muthuraman Muthuraman , Mohammad Badr , Lisa Harder-Rauschenberger , Fabian Kremer , Selin Asci , Sophie Steinhauser , Ann-Kathrin Karl , Jonathan M. Brotchie , James B. Koprich , Jens Volkmann , Chi Wang Ip
{"title":"Deep brain stimulation halts Parkinson’s disease-related immune dysregulation in the brain and peripheral blood","authors":"Rhonda L. McFleder , Thomas Musacchio , Johanna Keller , Susanne Knorr , Tobias Petschner , Jia Zhi Chen , Muthuraman Muthuraman , Mohammad Badr , Lisa Harder-Rauschenberger , Fabian Kremer , Selin Asci , Sophie Steinhauser , Ann-Kathrin Karl , Jonathan M. Brotchie , James B. Koprich , Jens Volkmann , Chi Wang Ip","doi":"10.1016/j.bbi.2024.10.039","DOIUrl":"10.1016/j.bbi.2024.10.039","url":null,"abstract":"<div><div>Immune dysregulation in the brain and periphery is thought to contribute to the detrimental neurodegeneration that occurs in Parkinson’s disease (PD). Identifying mechanisms to reverse this dysregulation is key to developing disease-altering therapeutics for this currently incurable disease. Here we utilized the longitudinal data from the Parkinson’s Progression Marker Initiative to demonstrate that circulating lymphocytes progressively decline in PD and can be used to predict future motor symptom progression. Deep brain stimulation (DBS), which is used as a symptomatic treatment, could halt this progressive decline. By analyzing specific immune populations from a second cohort of patients, we could show that DBS causes a shift from the pro-inflammatory CD4<sup>+</sup> T helper 17 cells driving neurodegeneration to anti-inflammatory CD4<sup>+</sup> regulatory T cells. RNA-sequencing and immunohistochemistry in the brain of the A53T alpha-synuclein rat model of PD revealed that DBS also decreases neuroinflammation. These data suggest a potential disease-altering role for DBS by halting inflammatory processes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 851-862"},"PeriodicalIF":8.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557203","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}
Weiqing Jiang , Yitong He , Qianyu Liu , Shuyi Peng , Yanyan Ni , Xiali Zhong , Lan Guo
{"title":"Associations between childhood maltreatment, peripheral immune biomarkers, and psychiatric symptoms in adults: A cohort study of over 138,000 participants","authors":"Weiqing Jiang , Yitong He , Qianyu Liu , Shuyi Peng , Yanyan Ni , Xiali Zhong , Lan Guo","doi":"10.1016/j.bbi.2024.10.034","DOIUrl":"10.1016/j.bbi.2024.10.034","url":null,"abstract":"<div><h3>Background</h3><div>Few studies have integrated the impact of individual and cumulative childhood maltreatment on multiple psychiatric symptoms, with the mechanisms underlying these associations largely unknown. This study aims to comprehensively assess the associations between childhood maltreatment, multiple peripheral immune biomarkers, and various psychiatric symptoms in adulthood and to explore whether peripheral immune inflammation plays a mediator role in the associations between childhood maltreatment and psychiatric symptoms in adulthood.</div></div><div><h3>Methods</h3><div>Using data from the UK Biobank, we constructed a retrospective cohort study of 138,915 participants who provided self-reported childhood maltreatment and had peripheral immune biomarkers assessed. We examined seven types of psychiatric symptoms in adulthood, including depressive symptoms, anxiety symptoms, mania, post-traumatic stress disorder (PTSD), psychotic experiences, self-harm, and alcohol use disorder. Logistic regression models were performed to explore the associations between childhood maltreatment, immune biomarkers, and psychiatric symptoms, calculating the average marginal effects for each indicator of childhood maltreatment. Mediation analyses were conducted to determine the extent to which the immune biomarkers could explain the association between childhood maltreatment and psychiatric symptoms in adulthood. Subgroup and sensitivity analyses were also performed.</div></div><div><h3>Results</h3><div>Among the participants, 77,937 (56.10 %) were female, with a mean age of 55.91 (SD: 7.73) years at baseline. There were dose–response relationships existed between the accumulation of childhood maltreatment indicators and all seven assessed psychiatric symptoms and multimorbidity in adulthood (e.g., for depressive symptoms, OR = 1.67 [95 %CI, 1.57 to 1.78] for one childhood maltreatment indicator; OR = 2.77 [95 % CI, 2.58 to 2.97] for two; OR = 4.91 [95 % CI, 4.61 to 5.24] for three or more). Emotional abuse and physical neglect showed the strongest average marginal effects on psychiatric symptoms. Levels of C-reactive protein (CRP) and counts of leukocytes and neutrophils were positively associated with depressive symptoms (e.g., OR = 1.13 [95 % CI, 1.08 to 1.17] for CRP level), anxiety symptoms, PTSD, and psychotic experiences. Moreover, levels of CRP partially mediated the association between childhood maltreatment scores and psychiatric symptoms, albeit with a relatively low mediation proportion (0.65 %-1.77 %).</div></div><div><h3>Conclusions</h3><div>Our findings underscore the importance of interventions that address multiple forms of childhood maltreatment to mitigate long-term mental health challenges substantially. While peripheral immunity responses may serve as predictors of mental health problems, they might not to be the primary mechanism through which childhood maltreatment influences psychiatric symptoms in adulthood.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 840-850"},"PeriodicalIF":8.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543762","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}