Pub Date : 2024-11-13DOI: 10.1016/j.bbi.2024.11.011
Kiruthika Ganesan, Sahar Ghorbanpour, William Kendall, Sarah Thomas Broome, Joanne M Gladding, Amolika Dhungana, Arvie Rodriguez Abiero, Maedeh Mahmoudi, Alessandro Castorina, Michael D Kendig, Serena Becchi, Veronika Valova, Louise Cole, Laura A Bradfield
Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, lipopolysaccharide-induced hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that LPS-induced hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.
{"title":"Hippocampal neuroinflammation induced by lipopolysaccharide causes sex-specific disruptions in action selection, food approach memories, and neuronal activation.","authors":"Kiruthika Ganesan, Sahar Ghorbanpour, William Kendall, Sarah Thomas Broome, Joanne M Gladding, Amolika Dhungana, Arvie Rodriguez Abiero, Maedeh Mahmoudi, Alessandro Castorina, Michael D Kendig, Serena Becchi, Veronika Valova, Louise Cole, Laura A Bradfield","doi":"10.1016/j.bbi.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.bbi.2024.11.011","url":null,"abstract":"<p><p>Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, lipopolysaccharide-induced hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that LPS-induced hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638378","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 : 2024-11-13DOI: 10.1016/j.bbi.2024.11.013
Tatlock H. Lauten , Safwan K. Elkhatib , Tamara Natour , Emily C. Reed , Caroline N. Jojo , Adam J. Case
Background
Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a mouse model of repeated social defeat stress (RSDS) that recapitulates certain features of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear.
Methods
Using a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., TH17).
Results
Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes.
Conclusions
Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of TH17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.
背景：创伤后应激障碍（PTSD创伤后应激障碍（PTSD）是一种使人衰弱的心理疾病，同时也表现为神经免疫异常。患者交感神经张力升高，继发自身免疫性疾病的风险增加。此前，我们曾利用一种能再现创伤后应激障碍某些特征的小鼠重复社会挫败应激（RSDS）模型，证明消除交感神经对T淋巴细胞的信号传导会特别限制它们产生促炎性白细胞介素17A（IL-17A）的能力；这种细胞因子与许多自身免疫性疾病的发展有牵连。然而，交感神经信号与T淋巴细胞产生IL-17A的机制仍不清楚：方法：我们使用可同时检测男性和女性的改良版 RSDS 以及 T 淋巴细胞极化的体外模型，评估了肾上腺素能受体阻断（遗传学和药理学）和儿茶酚胺耗竭对 T 淋巴细胞分化为产生 IL-17A 的亚型（即 TH17）的影响和机制：结果：只有对β1和2肾上腺素能受体（β1/2）的药理抑制能显著降低RSDS后的循环IL-17A水平，但对其他促炎细胞因子（如IL-6、TNF-α和IL-10）没有影响。这一发现通过使用全基因β1/2受体敲除小鼠的RSDS以及将β1/2基因敲除的T淋巴细胞收养性转移到免疫缺陷宿主体内得到了证实。即使在没有外源性交感神经递质补充的情况下，体内极化的T淋巴细胞在β1/2信号被阻断后产生的IL-17A也明显减少，这表明T淋巴细胞产生的儿茶酚胺可能参与了IL-17A的产生。此外，环磷酸腺苷（cAMP）被证明在机理上参与了驱动 T 淋巴细胞产生 IL-17A 的过程，而扩大 cAMP 信号转导可恢复因缺乏 β1/2 信号转导而导致的 IL-17A 缺失。最后，即使在IL-17A极化条件下，去除β1/2和cAMP信号也能促进调节性T淋巴细胞（Treg）的极化，这表明肾上腺素能信号在促炎和抗炎T淋巴细胞亚型之间的转换中发挥作用：我们的数据描述了β1/2肾上腺素能和cAMP信号在TH17/Treg淋巴细胞平衡中的新作用。这些发现为与 IL-17A 相关病理相关的精神疾病和自身免疫性疾病的药物治疗提供了新的靶点。
{"title":"TH17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling","authors":"Tatlock H. Lauten , Safwan K. Elkhatib , Tamara Natour , Emily C. Reed , Caroline N. Jojo , Adam J. Case","doi":"10.1016/j.bbi.2024.11.013","DOIUrl":"10.1016/j.bbi.2024.11.013","url":null,"abstract":"<div><h3>Background</h3><div>Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a mouse model of repeated social defeat stress (RSDS) that recapitulates certain features of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear.</div></div><div><h3>Methods</h3><div>Using a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., T<sub>H</sub>17).</div></div><div><h3>Results</h3><div>Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g.,<!--> <!-->IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes.</div></div><div><h3>Conclusions</h3><div>Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of T<sub>H</sub>17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1061-1070"},"PeriodicalIF":8.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615078","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 : 2024-11-13DOI: 10.1016/j.bbi.2024.11.018
Danielle N. Clark , Shelby V. Brown , Li Xu , Rae-Ling Lee , Joey V. Ragusa , Zhenghao Xu , Joshua D. Milner , Anthony J. Filiano
The interferon (IFN)-induced STAT1 signaling pathway is a canonical immune pathway that has also been implicated in regulating neuronal activity. The pathway is enriched in brains of individuals with autism spectrum disorder (ASD) and schizophrenia (SZ). Over-activation of the STAT1 pathway causes pathological transcriptional responses, however it is unclear how these responses might translate into behavioral phenotypes. We hypothesized that prolonged STAT1 signaling in neurons would be sufficient to cause behavioral deficits associated with neurodevelopmental disorders. In this study, we developed a novel mouse model with the clinical STAT1 gain-of-function mutation, T385M, in neurons. These mice were hyperactive and displayed neural hypoactivity with less neuron counts in the caudate putamen. Driving the STAT1 gain-of-function mutation exclusively in dopaminergic neurons, which project to the caudate putamen of the dorsal striatum, mimicked some hyperactive behaviors without a reduction of neurons. Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 signaling in all excitatory or inhibitory neurons or in microglia were not hyperactive. Overall, these findings suggest that STAT1 signaling in neurons is a crucial player in regulating striatal neuron activity and aspects of motor behavior.
{"title":"Prolonged STAT1 signaling in neurons causes hyperactive behavior","authors":"Danielle N. Clark , Shelby V. Brown , Li Xu , Rae-Ling Lee , Joey V. Ragusa , Zhenghao Xu , Joshua D. Milner , Anthony J. Filiano","doi":"10.1016/j.bbi.2024.11.018","DOIUrl":"10.1016/j.bbi.2024.11.018","url":null,"abstract":"<div><div>The interferon (IFN)-induced STAT1 signaling pathway is a canonical immune pathway that has also been implicated in regulating neuronal activity. The pathway is enriched in brains of individuals with autism spectrum disorder (ASD) and schizophrenia (SZ). Over-activation of the STAT1 pathway causes pathological transcriptional responses, however it is unclear how these responses might translate into behavioral phenotypes. We hypothesized that prolonged STAT1 signaling in neurons would be sufficient to cause behavioral deficits associated with neurodevelopmental disorders. In this study, we developed a novel mouse model with the clinical STAT1 gain-of-function mutation, T385M, in neurons. These mice were hyperactive and displayed neural hypoactivity with less neuron counts in the caudate putamen. Driving the STAT1 gain-of-function mutation exclusively in dopaminergic neurons, which project to the caudate putamen of the dorsal striatum, mimicked some hyperactive behaviors without a reduction of neurons. Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 signaling in all excitatory or inhibitory neurons or in microglia were not hyperactive. Overall, these findings suggest that STAT1 signaling in neurons is a crucial player in regulating striatal neuron activity and aspects of motor behavior.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 1-8"},"PeriodicalIF":8.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615077","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 : 2024-11-10DOI: 10.1016/j.bbi.2024.11.016
Kang Chen , Qingqing Ye , Yanqun Zhang , Zhenhua Qi , Yue Huang , Weicheng Lu , Xintong Wang , Yuting Wang , Lan Cao , Shijuan Qiu , Yixin Xu , Junting Huang , Jingdun Xie
Pancreatic cancer can cause severe abdominal pain. Its peripheral mechanisms have been studied, but the role of central nervous system in pancreatic cancer-induced pain remains unclear. The current study focused on the nucleus tractus solitarii (NTS), a primary center of visceral sensation located in medulla oblongata. Neurons in the NTS were activated and exhibited increased excitability among mice with pancreatic cancer-induced pain. Transcriptome analysis revealed that pancreatic cancer-induced pain was associated with neuroinflammation in the NTS, involving changes in chemokines expression. In mice with pancreatic cancer-induced pain, the microglia activation in the NTS was observed, characterized by increased cell density and decreased process number and length, while injection of microglia inhibitor minocycline in the NTS alleviated pancreatic cancer-induced pain. The cytokine CXCL1 and its receptor CXCR2 were upregulated in the NTS of mice with pancreatic cancer-induced pain. Blocking CXCL1-CXCR2 signaling by injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 in the NTS of mice with pancreatic cancer-induced pain alleviated abdominal hypersensitivity and hunching behavior, and also reversed the activation of neurons and microglia. Additionally, injection of recombinant CXCL1 in the NTS of sham-operated mice induced abdominal pain, and activated the neurons and microglia. In summary, our study highlights the critical role of NTS microglia activation mediated by CXCL1-CXCR2 signaling in pancreatic cancer-induced pain.
{"title":"CXCL1-CXCR2 signaling mediates the activation of microglia in the nucleus tractus solitarii to promote pancreatic cancer-induced pain","authors":"Kang Chen , Qingqing Ye , Yanqun Zhang , Zhenhua Qi , Yue Huang , Weicheng Lu , Xintong Wang , Yuting Wang , Lan Cao , Shijuan Qiu , Yixin Xu , Junting Huang , Jingdun Xie","doi":"10.1016/j.bbi.2024.11.016","DOIUrl":"10.1016/j.bbi.2024.11.016","url":null,"abstract":"<div><div>Pancreatic cancer can cause severe abdominal pain. Its peripheral mechanisms have been studied, but the role of central nervous system in pancreatic cancer-induced pain remains unclear. The current study focused on the nucleus tractus solitarii (NTS), a primary center of visceral sensation located in medulla oblongata. Neurons in the NTS were activated and exhibited increased excitability among mice with pancreatic cancer-induced pain. Transcriptome analysis revealed that pancreatic cancer-induced pain was associated with neuroinflammation in the NTS, involving changes in chemokines expression. In mice with pancreatic cancer-induced pain, the microglia activation in the NTS was observed, characterized by increased cell density and decreased process number and length, while injection of microglia inhibitor minocycline in the NTS alleviated pancreatic cancer-induced pain. The cytokine CXCL1 and its receptor CXCR2 were upregulated in the NTS of mice with pancreatic cancer-induced pain. Blocking CXCL1-CXCR2 signaling by injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 in the NTS of mice with pancreatic cancer-induced pain alleviated abdominal hypersensitivity and hunching behavior, and also reversed the activation of neurons and microglia. Additionally, injection of recombinant CXCL1 in the NTS of sham-operated mice induced abdominal pain, and activated the neurons and microglia. In summary, our study highlights the critical role of NTS microglia activation mediated by CXCL1-CXCR2 signaling in pancreatic cancer-induced pain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1026-1041"},"PeriodicalIF":8.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615093","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 : 2024-11-10DOI: 10.1016/j.bbi.2024.11.012
Neel Patel, Joseph Rios, Retwika Ganguly, Cindy Mutafoglu, Nour Shalash, Karla Gallardo, Malak Saleh, John Chahine, Emily Kopecky, Gursimran Gujral, Kamya Shah, Christos Suriano
Animals face the risk of encountering pathogenic microbes while foraging for resources. Assessing the risk of nutrition vs. infection can result in the behavioral regulation of immune processes. Behavioral immunity in the nematode roundworm Caenorhabditis elegans (C. elegans) is regulated, in part, by the innate immune molecule TOL-1: a homolog of vertebrate Toll-like Receptor (TLR) proteins that influences C. elegans pathogen avoidance behaviors by promoting the development of CO2-detecting chemosensory neurons. While TOL-1's role in pathogen avoidance is well established, its role in an opposing behavior - foraging - has not been examined. In addition to pathogenic bacteria, preferred food for C. elegans, such as Escherichia coli (E. coli), create significant and aversive environmental CO2 levels which may limit feeding behaviors in a tol-1 dependent manner. We have found that in addition to conferring antibacterial immunity, TOL-1 signals in neurons through the p38 MAPK PMK-1 to promote turning behavior and limit foraging when food is abundant and that the anorectic TOL-1/PMK-1 pathway is attenuated during starvation to promote foraging These data highlight the dynamic role of a conserved innate immune cascade in neurons during both high and low hunger states and identify mechanisms underlying the neuro-immune control of feeding strategies.
{"title":"Toll-like receptor signaling in neurons modulates C. elegans feeding behavior in a hunger state-dependent manner.","authors":"Neel Patel, Joseph Rios, Retwika Ganguly, Cindy Mutafoglu, Nour Shalash, Karla Gallardo, Malak Saleh, John Chahine, Emily Kopecky, Gursimran Gujral, Kamya Shah, Christos Suriano","doi":"10.1016/j.bbi.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.bbi.2024.11.012","url":null,"abstract":"<p><p>Animals face the risk of encountering pathogenic microbes while foraging for resources. Assessing the risk of nutrition vs. infection can result in the behavioral regulation of immune processes. Behavioral immunity in the nematode roundworm Caenorhabditis elegans (C. elegans) is regulated, in part, by the innate immune molecule TOL-1: a homolog of vertebrate Toll-like Receptor (TLR) proteins that influences C. elegans pathogen avoidance behaviors by promoting the development of CO<sub>2</sub>-detecting chemosensory neurons. While TOL-1's role in pathogen avoidance is well established, its role in an opposing behavior - foraging - has not been examined. In addition to pathogenic bacteria, preferred food for C. elegans, such as Escherichia coli (E. coli), create significant and aversive environmental CO<sub>2</sub> levels which may limit feeding behaviors in a tol-1 dependent manner. We have found that in addition to conferring antibacterial immunity, TOL-1 signals in neurons through the p38 MAPK PMK-1 to promote turning behavior and limit foraging when food is abundant and that the anorectic TOL-1/PMK-1 pathway is attenuated during starvation to promote foraging These data highlight the dynamic role of a conserved innate immune cascade in neurons during both high and low hunger states and identify mechanisms underlying the neuro-immune control of feeding strategies.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615092","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 : 2024-11-10DOI: 10.1016/j.bbi.2024.11.014
Danielle HJ Kim , Lisa A Croen , Ana-Maria Iosif , Jennifer L Ames , Stacey Alexeeff , Yinge Qian , Robert H Yolken , Paul Ashwood , Judy Van de Water
<div><div>Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID+] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID+ mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID+ mothers had significantly higher levels of IL-22 (estimate [est.] = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (est. = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID+ mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (hazard ratio [HR] = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns
{"title":"The association of maternal COVID-19-infection during pregnancy on the neonatal immune profile and associations with later diagnosis of neurodevelopmental disorders","authors":"Danielle HJ Kim , Lisa A Croen , Ana-Maria Iosif , Jennifer L Ames , Stacey Alexeeff , Yinge Qian , Robert H Yolken , Paul Ashwood , Judy Van de Water","doi":"10.1016/j.bbi.2024.11.014","DOIUrl":"10.1016/j.bbi.2024.11.014","url":null,"abstract":"<div><div>Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID+] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID+ mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID+ mothers had significantly higher levels of IL-22 (estimate [est.] = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (est. = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID+ mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (hazard ratio [HR] = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1071-1080"},"PeriodicalIF":8.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615091","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 : 2024-11-10DOI: 10.1016/j.bbi.2024.11.017
Jonathan Savitz , Brett A. McKinney , Timothy B. Meier , Haixia Zheng , Bart N. Ford , Robert H. Yolken , T.Kent Teague , Steve W. Cole
Altered activity of major immunoregulatory pathways has been reported in major depressive disorder (MDD) and is thought to underlie the elevations in circulating inflammatory mediators present in a subgroup of patients. However, the drivers of these changes in gene expression remain unclear. One potential modulator of immune function is viral infection. Here we examined the relationship between cytomegalovirus (CMV), a common herpesvirus, that has been shown to be a pathological cofactor in inflammatory disorders, and activity of key coordinators of the innate inflammatory response in MDD. We used RNAseq to characterize gene expression differences in in 79 unmedicated individuals with MDD and 80 healthy controls (HCs). A well-established bioinformatic strategy was used to quantify transcription control pathway activity based on the relative prevalence of pre-specified transcription factor-binding motifs in the promoters of differentially expressed genes. The main aim was to characterize diagnostic differences in immunoregulatory pathway activity and determine if these were related to CMV serostatus or antibody titer (viral reactivation). Significantly increased activity of interferon regulatory factor 1 (IRF1) and nuclear factor kappa-B cell (NF-κB) pathways was observed in the MDD group compared with HCs. Transcript Origin Analyses using cell-specific reference transcriptomes indicated that the MDD-associated transcriptome changes derived primarily from myeloid lineage immune cells (classical and non-classical monocytes). A more modest MDD-associated upregulation of glucocorticoid receptor (GR) pathway activity was also present. CMV infection/activity across the combined MDD and HC groups was weakly related to GR pathway activation but not to IRF1 and NF-κB activity; the most salient signature of CMV was activation and/or expansion of the CD8+ T-cell population. The elevated MDD-associated NF-κB (but not IRF1) activity was markedly attenuated after controlling for CMV antibody titer or for CD8+ T-cell prevalence. At least some of the NF-κB signal in MDD may be attributable to the cellular immune response to CMV, suggesting that CMV infection may be one of several pathways contributing to inflammation in depression. The pronounced activation of the antiviral IRF-1 pathway in MDD suggests the contribution of viral processes although this specific antiviral effect was not specific to CMV. CMV may indirectly drive interferon responses by impairing T-cell control of other viral infections.
{"title":"Nuclear factor kappa-B cell (NF-κB), interferon regulatory Factor, and glucocorticoid receptor pathway activation in major depressive Disorder: The role of cytomegalovirus infection","authors":"Jonathan Savitz , Brett A. McKinney , Timothy B. Meier , Haixia Zheng , Bart N. Ford , Robert H. Yolken , T.Kent Teague , Steve W. Cole","doi":"10.1016/j.bbi.2024.11.017","DOIUrl":"10.1016/j.bbi.2024.11.017","url":null,"abstract":"<div><div>Altered activity of major immunoregulatory pathways has been reported in major depressive disorder (MDD) and is thought to underlie the elevations in circulating inflammatory mediators present in a subgroup of patients. However, the drivers of these changes in gene expression remain unclear. One potential modulator of immune function is viral infection. Here we examined the relationship between cytomegalovirus (CMV), a common herpesvirus, that has been shown to be a pathological cofactor in inflammatory disorders, and activity of key coordinators of the innate inflammatory response in MDD. We used RNAseq to characterize gene expression differences in in 79 unmedicated individuals with MDD and 80 healthy controls (HCs). A well-established bioinformatic strategy was used to quantify transcription control pathway activity based on the relative prevalence of pre-specified transcription factor-binding motifs in the promoters of differentially expressed genes. The main aim was to characterize diagnostic differences in immunoregulatory pathway activity and determine if these were related to CMV serostatus or antibody titer (viral reactivation). Significantly increased activity of interferon regulatory factor 1 (IRF1) and nuclear factor kappa-B cell (NF-κB) pathways was observed in the MDD group compared with HCs. Transcript Origin Analyses using cell-specific reference transcriptomes indicated that the MDD-associated transcriptome changes derived primarily from myeloid lineage immune cells (classical and non-classical monocytes). A more modest MDD-associated upregulation of glucocorticoid receptor (GR) pathway activity was also present. CMV infection/activity across the combined MDD and HC groups was weakly related to GR pathway activation but not to IRF1 and NF-κB activity; the most salient signature of CMV was activation and/or expansion of the CD8+ T-cell population. The elevated MDD-associated NF-κB (but not IRF1) activity was markedly attenuated after controlling for CMV antibody titer or for CD8+ T-cell prevalence. At least some of the NF-κB signal in MDD may be attributable to the cellular immune response to CMV, suggesting that CMV infection may be one of several pathways contributing to inflammation in depression. The pronounced activation of the antiviral IRF-1 pathway in MDD suggests the contribution of viral processes although this specific antiviral effect was not specific to CMV.<!--> <!-->CMV may indirectly drive interferon responses by impairing T-cell control of other viral infections.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1052-1060"},"PeriodicalIF":8.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615094","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 : 2024-11-06DOI: 10.1016/j.bbi.2024.11.005
Huan Yang , Yun-Yun Wang , Weiqi Chang , Mengying Zhai , Wan-Jie Du , Wencheng Jiang , Yan-Wei Xiang , Guoyou Qin , Jin Yu , Ye Gong , Qingjian Han
Psoriasis, a chronic autoimmune skin condition with significant global morbidity, badly impairs patients’ quality of life. Stress has been identified as a prominent trigger for psoriasis, and effectively management of stress can ameliorate its pathological manifestations. However, the precise mechanisms by which stress influences psoriasis remain elusive. In this study, we found that mice subjected to chronic social defeat stress (CSDS) exhibit severer imiquimod (IMQ)-induced psoriasis with increased epidermal scaling, epidermal hyperplasia, number of epidermal ridges, itch, and skin inflammation than control mice. Mechanistic study reveals that CSDS leads to an elevated release of miR-let-7b, an endogenous ligand of Toll-like receptor 7 (TLR7), from the peripheral terminal of dorsal root ganglia (DRG) neurons into the skin. This process can stimulate skin-resident macrophages to release cytokines (such as IL-6 and TNF-a) and chemokines (such as MCP-1), subsequently promoting the recruitment of additional macrophages into the skin. Notably, the specific blockade of miR-let-7b in DRG neurons effectively relieve stress-induced exacerbations of psoriasis. Furthermore, intradermal injection of synthetic miR-let-7b can induce a psoriasis-like phenotype in wildtype mice, a phenomenon that can be countered by the application of a TLR7 antagonist. Additionally, microfluidic chamber coculture assays demonstrated that miR-let-7b released by DRG neurons activates macrophages via TLR7 expressed on these immune cells. Totally, this study found that stress-induced upregulation and release of miR-let-7b from DRG neurons stimulates macrophages to secrete more inflammatory cytokines and chemokines, thereby exacerbating skin inflammation and the psoriatic phenotype. These findings provide a potential therapeutic strategy targeting the miR-let-7b/TLR7 pathway to alleviate stress-induced exacerbation of psoriasis.
{"title":"Primary sensory neuron-derived miR-let-7b underlies stress-elicited psoriasis","authors":"Huan Yang , Yun-Yun Wang , Weiqi Chang , Mengying Zhai , Wan-Jie Du , Wencheng Jiang , Yan-Wei Xiang , Guoyou Qin , Jin Yu , Ye Gong , Qingjian Han","doi":"10.1016/j.bbi.2024.11.005","DOIUrl":"10.1016/j.bbi.2024.11.005","url":null,"abstract":"<div><div>Psoriasis, a chronic autoimmune skin condition with significant global morbidity, badly impairs patients’ quality of life. Stress has been identified as a prominent trigger for psoriasis, and effectively management of stress can ameliorate its pathological manifestations. However, the precise mechanisms by which stress influences psoriasis remain elusive. In this study, we found that mice subjected to chronic social defeat stress (CSDS) exhibit severer imiquimod (IMQ)-induced psoriasis with increased epidermal scaling, epidermal hyperplasia, number of epidermal ridges, itch, and skin inflammation than control mice. Mechanistic study reveals that CSDS leads to an elevated release of miR-let-7b, an endogenous ligand of Toll-like receptor 7 (TLR7), from the peripheral terminal of dorsal root ganglia (DRG) neurons into the skin. This process can stimulate skin-resident macrophages to release cytokines (such as IL-6 and TNF-a) and chemokines (such as MCP-1), subsequently promoting the recruitment of additional macrophages into the skin. Notably, the specific blockade of miR-let-7b in DRG neurons effectively relieve stress-induced exacerbations of psoriasis. Furthermore, intradermal injection of synthetic miR-let-7b can induce a psoriasis-like phenotype in wildtype mice, a phenomenon that can be countered by the application of a TLR7 antagonist. Additionally, microfluidic chamber coculture assays demonstrated that miR-let-7b released by DRG neurons activates macrophages via TLR7 expressed on these immune cells. Totally, this study found that stress-induced upregulation and release of miR-let-7b from DRG neurons stimulates macrophages to secrete more inflammatory cytokines and chemokines, thereby exacerbating skin inflammation and the psoriatic phenotype. These findings provide a potential therapeutic strategy targeting the miR-let-7b/TLR7 pathway to alleviate stress-induced exacerbation of psoriasis.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 997-1010"},"PeriodicalIF":8.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603230","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 : 2024-11-05DOI: 10.1016/j.bbi.2024.11.010
Anni Niskanen , Aaron Barron , Hatim Azaryah , Martta Kerkelä , Elmo Pulli , Jetro J. Tuulari , Minna Lukkarinen , Linnea Karlsson , Ryan L. Muetzel , Cristina Campoy , Andrés Catena , Henning Tiemeier , Golam M. Khandaker , Hasse Karlsson , Juha Veijola , Lassi Björnholm
Maternal immune activation (MIA) during pregnancy is implicated in offspring psychiatric disorders. However, it is unknown to what extent MIA affects neurodevelopment, particularly cerebrocortical anatomy, in the general population, and whether effects differ by sex. The current study used vertex-wise statistics to examine the association between maternal prenatal CRP, an archetypal systemic inflammatory marker, and offspring cortical thickness, surface area, and volume, in 2635 mother–child dyads (5.4–26.5 years) from three population-based cohorts, and one clinical cohort enriched for presence of inflammation markers.
Maternal CRP within a normal physiological range (<10 mg/L) exhibited sex-specific quadratic associations with cortical morphological measures in 2 regions in males and 1 region in females at childhood. Elevated (>10 mg/L) CRP was associated with regional cortical morphology in females and in a pooled sample of sexes. Overall, MIA is associated with cortical development in a regional and sex-specific manner in studies spanning childhood to adulthood.
{"title":"Sex-specific associations between maternal prenatal inflammation and offspring cortical morphology in youth: A harmonised study across four birth cohorts","authors":"Anni Niskanen , Aaron Barron , Hatim Azaryah , Martta Kerkelä , Elmo Pulli , Jetro J. Tuulari , Minna Lukkarinen , Linnea Karlsson , Ryan L. Muetzel , Cristina Campoy , Andrés Catena , Henning Tiemeier , Golam M. Khandaker , Hasse Karlsson , Juha Veijola , Lassi Björnholm","doi":"10.1016/j.bbi.2024.11.010","DOIUrl":"10.1016/j.bbi.2024.11.010","url":null,"abstract":"<div><div>Maternal immune activation (MIA) during pregnancy is implicated in offspring psychiatric disorders. However, it is unknown to what extent MIA affects neurodevelopment, particularly cerebrocortical anatomy, in the general population, and whether effects differ by sex. The current study used vertex-wise statistics to examine the association between maternal prenatal CRP, an archetypal systemic inflammatory marker, and offspring cortical thickness, surface area, and volume, in 2635 mother–child dyads (5.4–26.5 years) from three population-based cohorts, and one clinical cohort enriched for presence of inflammation markers.</div><div>Maternal CRP within a normal physiological range (<10 mg/L) exhibited sex-specific quadratic associations with cortical morphological measures in 2 regions in males and 1 region in females at childhood. Elevated (>10 mg/L) CRP was associated with regional cortical morphology in females and in a pooled sample of sexes. Overall, MIA is associated with cortical development in a regional and sex-specific manner in studies spanning childhood to adulthood.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 1081-1090"},"PeriodicalIF":8.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589777","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 : 2024-11-04DOI: 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}
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