Pub Date : 2025-12-18DOI: 10.1016/j.bbi.2025.106223
Shivangi Jain , Patricio Solis-Urra , Alina Lesnovskaya , Lu Wan , Cristina Molina-Hidalgo , Audrey Collins , Haiqing Huang , Kelsey R. Sewell , Rebecca Reed , Renee J. Rogers , Anna L. Marsland , George Grove , Lauren E. Oberlin , Chaeryon Kang , John M. Jakicic , Lauren Raine , Joseph Mettenburg , Lauren M. Sparks , Arthur F. Kramer , Charles Hillman , Kirk I. Erickson
White matter hyperintensities or lesions (WMLs) increase the risk for cognitive impairment and dementia. Cardiometabolic factors (e.g., excess adiposity) and markers of systemic inflammation relate to greater WML volume, but few studies have examined whether specific compartments of adipose tissue (e.g., visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT)) relative to total body adiposity (TBA) differentially relate to WML volume or whether these patterns could be statistically mediated by inflammation. We examined associations between markers of low-grade systemic inflammation and compartments of adipose tissue relative to total body adiposity (rVAT or rASAT respectively), measured by dual-energy x-ray absorptiometry (DXA), and WML volume. We hypothesized that higher rVAT and not rASAT would be associated with greater WML volume, and that this association would be statistically mediated by concentrations of inflammatory cytokines. We used baseline data (n = 648) from the multisite study “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE; mean age = 69.9 ± 3.8 years, 70.5 % females). IL-6, IL-1RA, and TNF-α were included as markers of systemic inflammation and age, sex, years of education, hypertension status, and study site were included as covariates. Our hypotheses were partially supported such that the relationship between rVAT and WMLs, as well as between rASAT and WMLs, were statistically mediated by IL-6 and TNF-α. These findings suggest that both higher rVAT and rASAT, are associated with higher WML burden through an elevated inflammatory state. These results set a testable mechanistic pathway for future longitudinal and intervention studies examining whether managing low-grade systemic inflammation and intentional weight loss would be beneficial for supporting brain health in older adults.
{"title":"Associations between white matter lesions, adiposity, and systemic inflammation in late adulthood: Results from the IGNITE study","authors":"Shivangi Jain , Patricio Solis-Urra , Alina Lesnovskaya , Lu Wan , Cristina Molina-Hidalgo , Audrey Collins , Haiqing Huang , Kelsey R. Sewell , Rebecca Reed , Renee J. Rogers , Anna L. Marsland , George Grove , Lauren E. Oberlin , Chaeryon Kang , John M. Jakicic , Lauren Raine , Joseph Mettenburg , Lauren M. Sparks , Arthur F. Kramer , Charles Hillman , Kirk I. Erickson","doi":"10.1016/j.bbi.2025.106223","DOIUrl":"10.1016/j.bbi.2025.106223","url":null,"abstract":"<div><div>White matter hyperintensities or lesions (WMLs) increase the risk for cognitive impairment and dementia. Cardiometabolic factors (e.g., excess adiposity) and markers of systemic inflammation relate to greater WML volume, but few studies have examined whether specific compartments of adipose tissue (e.g., visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT)) relative to total body adiposity (TBA) differentially relate to WML volume or whether these patterns could be statistically mediated by inflammation. We examined associations between markers of low-grade systemic inflammation and compartments of adipose tissue relative to total body adiposity (rVAT or rASAT respectively), measured by dual-energy x-ray absorptiometry (DXA), and WML volume. We hypothesized that higher rVAT and not rASAT would be associated with greater WML volume, and that this association would be statistically mediated by concentrations of inflammatory cytokines. We used baseline data (n = 648) from the multisite study “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE; mean age = 69.9 ± 3.8 years, 70.5 % females). IL-6, IL-1RA, and TNF-α were included as markers of systemic inflammation and age, sex, years of education, hypertension status, and study site were included as covariates. Our hypotheses were partially supported such that the relationship between rVAT and WMLs, as well as between rASAT and WMLs, were statistically mediated by IL-6 and TNF-α. These findings suggest that both higher rVAT and rASAT, are associated with higher WML burden through an elevated inflammatory state. These results set a testable mechanistic pathway for future longitudinal and intervention studies examining whether managing low-grade systemic inflammation and intentional weight loss would be beneficial for supporting brain health in older adults.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106223"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800257","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106226
Adil El Mesaoudi , Abdelmoumen Kassoussi , Amina Zahaf , Maysoun Ayadi , Sara Naglieri , Corentine Marie , Ferechte Razavi , Pierre Bobé , Jelena Martinovic , Carlos Parras , Elisabeth Traiffort
The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.
{"title":"Smoothened-mediated signaling contributes to immune and non-immune functions of microglia","authors":"Adil El Mesaoudi , Abdelmoumen Kassoussi , Amina Zahaf , Maysoun Ayadi , Sara Naglieri , Corentine Marie , Ferechte Razavi , Pierre Bobé , Jelena Martinovic , Carlos Parras , Elisabeth Traiffort","doi":"10.1016/j.bbi.2025.106226","DOIUrl":"10.1016/j.bbi.2025.106226","url":null,"abstract":"<div><div>The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106226"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800356","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 : 2025-12-17DOI: 10.1016/j.bbi.2025.106222
Maria Elisa Caetano-Silva , Miranda E. Hilt , Ivan Valishev , Casey Lim , Mikaela Kasperek , Akriti Shrestha , Helen Fu , Eleanor Eck , Robert McCusker , Heather Armstrong , Brett Loman , Michael T. Bailey , Jacob M. Allen
Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either Citrobacter rodentium infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (Duox2), Dual oxidase maturation factor 2 (Duoxa2), and inducible nitric oxide synthase 2 (Nos2) in IECs (2- to 8-fold, p < 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α −diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (C. rodentium) and chemically induced (DSS) colitis, amplifying colonic expression of Duox2, Nos2, and Ccl2, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase–driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.
{"title":"Social stress worsens colitis through β-adrenergic–driven oxidative stress in intestinal mucosal compartments","authors":"Maria Elisa Caetano-Silva , Miranda E. Hilt , Ivan Valishev , Casey Lim , Mikaela Kasperek , Akriti Shrestha , Helen Fu , Eleanor Eck , Robert McCusker , Heather Armstrong , Brett Loman , Michael T. Bailey , Jacob M. Allen","doi":"10.1016/j.bbi.2025.106222","DOIUrl":"10.1016/j.bbi.2025.106222","url":null,"abstract":"<div><div>Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either <em>Citrobacter rodentium</em> infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (<em>Duox2</em>), Dual oxidase maturation factor 2 (<em>Duoxa2</em>), and inducible nitric oxide synthase 2 (<em>Nos2</em>) in IECs (2- to 8-fold, <em>p</em> < 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α −diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (<em>C. rodentium</em>) and chemically induced (DSS) colitis, amplifying colonic expression of <em>Duox2</em>, <em>Nos2</em>, and <em>Ccl2</em>, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase–driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106222"},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793402","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}
Excessive fructose intake is a growing public health concern, yet many individuals have a limited capacity to absorb typical dietary levels, leading to chronic fructose malabsorption and intestinal spillover. In animal models, this spillover disrupts the gut microbiota, but its impact in humans remains unexplored. We hypothesized that fructose malabsorption–induced dysbiosis contributes to peripheral inflammation, which, together with neuroinflammation, plays a role in mood disorders. This study investigates the link between fructose malabsorption, gut microbiota, and mood disorders in a human cohort, and explores their association with neuroinflammation in a Glut5 knockout (GLUT5_KO) mouse model of fructose-malabsorption.
In a human cohort of male healthy volunteers, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, GLUT5_KO male mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed.
Sixty percent of volunteers exhibited fructose malabsorption, along with elevated plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, GLUT5_KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes.
These findings highlight the complex interplay between dietary fructose, gut microbiota, low grade inflammation and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions.
{"title":"Fructose malabsorption induces dysbiosis and increases anxiety in male human and animal models","authors":"Adeline Coursan , Delphine Polve , Anne-Marie Leroi , Magali Monnoye , Lea Roussin , Clara Benatar , Marie-Pierre Tavolacci , Muriel Quillard Muraine , Mathilde Maccarone , Olivia Guérin , Estelle Houivet , Charlène Guérin , Valery Brunel , Jérôme Bellenger , Jean-Paul Pais de Barros , Guillaume Gourcerol , Laurent Naudon , Sophie Layé , Charlotte Madore , Xavier Fioramonti , Véronique Douard","doi":"10.1016/j.bbi.2025.106221","DOIUrl":"10.1016/j.bbi.2025.106221","url":null,"abstract":"<div><div>Excessive fructose intake is a growing public health concern, yet many individuals have a limited capacity to absorb typical dietary levels, leading to chronic fructose malabsorption and intestinal spillover. In animal models, this spillover disrupts the gut microbiota, but its impact in humans remains unexplored. We hypothesized that fructose malabsorption–induced dysbiosis contributes to peripheral inflammation, which, together with neuroinflammation, plays a role in mood disorders. This study investigates the link between fructose malabsorption, gut microbiota, and mood disorders in a human cohort, and explores their association with neuroinflammation in a <em>Glut5</em> knockout (GLUT5_KO) mouse model of fructose-malabsorption.</div><div>In a human cohort of male healthy volunteers, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, GLUT5_KO male mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed.</div><div>Sixty percent of volunteers exhibited fructose malabsorption, along with elevated plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, GLUT5_KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes.</div><div>These findings highlight the complex interplay between dietary fructose, gut microbiota, low grade inflammation and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106221"},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793369","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 : 2025-12-11DOI: 10.1016/j.bbi.2025.106217
Viacheslav A. Petrov , Sebastian Schade , Cedric C. Laczny , Jenny Hällqvist , Patrick May , Christian Jäger , Velma T.E. Aho , Oskar Hickl , Rashi Halder , Elisabeth Lang , Jordan Caussin , Laura A. Lebrun , Janine Schulz , Marcus Michael Unger , Kevin Mills , Brit Mollenhauer , Paul Wilmes
Alterations in the gut microbiome and a “leaky” gut are associated with Parkinson’s disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet.
Our findings reveal associations between dietary patterns and changes in the gut microbiome’s taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in Faecalibacterium species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD.
Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.
{"title":"Resistant starch improves Parkinson’s disease symptoms through restructuring of the gut microbiome and modulating inflammation","authors":"Viacheslav A. Petrov , Sebastian Schade , Cedric C. Laczny , Jenny Hällqvist , Patrick May , Christian Jäger , Velma T.E. Aho , Oskar Hickl , Rashi Halder , Elisabeth Lang , Jordan Caussin , Laura A. Lebrun , Janine Schulz , Marcus Michael Unger , Kevin Mills , Brit Mollenhauer , Paul Wilmes","doi":"10.1016/j.bbi.2025.106217","DOIUrl":"10.1016/j.bbi.2025.106217","url":null,"abstract":"<div><div>Alterations in the gut microbiome and a “leaky” gut are associated with Parkinson’s disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet.</div><div>Our findings reveal associations between dietary patterns and changes in the gut microbiome’s taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in <em>Faecalibacterium</em> species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD.</div><div>Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106217"},"PeriodicalIF":7.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751664","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 : 2025-12-10DOI: 10.1016/j.bbi.2025.106219
Junli Zhao , Runda Li , Yuqing Wang , Sharat Chandra , Vivian Zhang , Haichen Wang , Ru-Rong Ji
Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., Fkbp5). The antinociceptive effects of NPD1 were abolished in Gpr37−/− mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not Gpr37−/− mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.
{"title":"NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain","authors":"Junli Zhao , Runda Li , Yuqing Wang , Sharat Chandra , Vivian Zhang , Haichen Wang , Ru-Rong Ji","doi":"10.1016/j.bbi.2025.106219","DOIUrl":"10.1016/j.bbi.2025.106219","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., <em>Fkbp5</em>). The antinociceptive effects of NPD1 were abolished in <em>Gpr37<sup>−</sup>/<sup>−</sup></em> mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not <em>Gpr37<sup>−</sup></em>/<em><sup>−</sup></em> mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106219"},"PeriodicalIF":7.6,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741102","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 : 2025-12-09DOI: 10.1016/j.bbi.2025.106214
Wiesława Florek , Katarzyna Barłowska , Marta Marlena Ziętek , Rafał Radosław Starzyński , Pasqualino Loi , Silvestre Sampino
Neurodevelopmental disorders (ND) arise from a complex interaction between genetic and maternal environmental factors occurring during pregnancy and involving the immune system. Rodent models, particularly genetic and immune-based approaches, have significantly advanced our understanding of ND etiology and pathogenesis. However, translationally relevant large animal model of maternal immune activation, capable of recapitulating behavioral phenotypes and biomarker associations consistent with ND are missing. In this study, we aimed to model ND in sheep by inducing Maternal Immune Activation (MIA) in pregnant ewes, as prenatal infections are well-replicated environmental factors associated with an increased risk of ND in humans. Pregnant ewes were challenged with bacterial lipopolysaccharide (LPS) to induce MIA at either mid- or late pregnancy, and the lambs’ behaviors were monitored after birth. Moreover, we developed and validated a battery of behavioral assays (e.g., Isolation Test, V-Detour Test, and T-Maze) to assess ND-related behavioral domains in lambs, such as social attachment, spatial learning, inhibitory control, and cognitive flexibility. Lambs prenatally exposed to MIA exhibited selective impairments in cognitive domains, including learning, memory consolidation, and cognitive flexibility, while developmental milestones and core social behaviors, such as maternal bonding, remained unchanged. Importantly, individual differences in maternal inflammatory responses, particularly IL-6 levels, correlated with the severity of behavioral alterations in the offspring. The observed behavioral phenotypes and immunological correlations support the validity of the ovine model for studying ND and related behavioral disorders. Our findings lay the groundwork for using sheep in future mechanistic and preclinical research on neurodevelopmental disorders.
{"title":"The sheep as a translational model for neurodevelopmental disorders induced by prenatal maternal immune activation","authors":"Wiesława Florek , Katarzyna Barłowska , Marta Marlena Ziętek , Rafał Radosław Starzyński , Pasqualino Loi , Silvestre Sampino","doi":"10.1016/j.bbi.2025.106214","DOIUrl":"10.1016/j.bbi.2025.106214","url":null,"abstract":"<div><div>Neurodevelopmental disorders (ND) arise from a complex interaction between genetic and maternal environmental factors occurring during pregnancy and involving the immune system. Rodent models, particularly genetic and immune-based approaches, have significantly advanced our understanding of ND etiology and pathogenesis. However, translationally relevant large animal model of maternal immune activation, capable of recapitulating behavioral phenotypes and biomarker associations consistent with ND are missing. In this study, we aimed to model ND in sheep by inducing Maternal Immune Activation (MIA) in pregnant ewes, as prenatal infections are well-replicated environmental factors associated with an increased risk of ND in humans. Pregnant ewes were challenged with bacterial lipopolysaccharide (LPS) to induce MIA at either mid- or late pregnancy, and the lambs’ behaviors were monitored after birth. Moreover, we developed and validated a battery of behavioral assays (e.g., Isolation Test, V-Detour Test, and T-Maze) to assess ND-related behavioral domains in lambs, such as social attachment, spatial learning, inhibitory control, and cognitive flexibility. Lambs prenatally exposed to MIA exhibited selective impairments in cognitive domains, including learning, memory consolidation, and cognitive flexibility, while developmental milestones and core social behaviors, such as maternal bonding, remained unchanged. Importantly, individual differences in maternal inflammatory responses, particularly IL-6 levels, correlated with the severity of behavioral alterations in the offspring. The observed behavioral phenotypes and immunological correlations support the validity of the ovine model for studying ND and related behavioral disorders. Our findings lay the groundwork for using sheep in future mechanistic and preclinical research on neurodevelopmental disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106214"},"PeriodicalIF":7.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741127","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 : 2025-12-09DOI: 10.1016/j.bbi.2025.106218
Xin Liu , Jian Jiang , Shiying Lin , Wenqiang Ge , Qingxiao Tao , Suwen Liu , Ouyang Zhanmu , Yang Yang , Bao Chai , Jingyu Zhang , Man Li , Hongxiang Chen
Interleukin-17a (IL-17a) has been established as a master regulator of inflammatory cascades in psoriasis pathogenesis. Monoclonal antibodies targeting IL-17a have demonstrated significant efficacy in relieving psoriasis-related symptoms, including the rapid alleviation of chronic itching. However, whether IL-17a is involved in chronic psoriatic pruritus and the specific mechanisms of its action remain poorly understood. In this study, we demonstrate that IL-17a significantly exacerbates chronic itch in a murine model of psoriasis. Mechanistically, IL-17a upregulation in psoriatic skin tissues activated the IL-17a receptor (IL-17Ra) in sensory neurons, subsequently promoting the expression of IL-6 in dorsal root ganglion (DRG) neurons. This neuron-derived IL-6 is transported via sensory nerve fibers to the spinal dorsal horn (SDH), where it triggers astrocyte activation and subsequent IL-1β secretion to potentiates chronic itch signaling in psoriasis. Our findings uncover a neuroimmune circuit in which IL-17a-IL-17Ra signaling on sensory neurons mediates the propagation of pruritic signals from peripheral skin to the central nervous system, with spinal IL-6-astrocyte-IL-1β axis serving as an amplifier of psoriatic pruritus.
白细胞介素-17a （IL-17a）已被确定为银屑病发病过程中炎症级联反应的主要调节因子。靶向IL-17a的单克隆抗体在缓解银屑病相关症状，包括快速缓解慢性瘙痒方面具有显著疗效。然而，IL-17a是否参与慢性银屑病瘙痒及其作用的具体机制尚不清楚。在这项研究中，我们证明IL-17a显著加重银屑病小鼠模型的慢性瘙痒。机制上，银屑病皮肤组织中IL-17a的上调激活了感觉神经元中的IL-17a受体（IL-17Ra），随后促进了背根神经节（DRG）神经元中IL-6的表达。这种神经元来源的IL-6通过感觉神经纤维运输到脊髓背角（SDH），在那里它触发星形胶质细胞激活和随后的IL-1β分泌，从而增强牛皮癣的慢性瘙痒信号。我们的发现揭示了一个神经免疫回路，其中感觉神经元上的IL-17a-IL-17Ra信号介导瘙痒信号从周围皮肤到中枢神经系统的传播，脊髓il -6星形细胞- il -1β轴作为银屑病瘙痒的放大器。
{"title":"From skin to spinal Cord: How IL-17a Drives psoriatic chronic itch","authors":"Xin Liu , Jian Jiang , Shiying Lin , Wenqiang Ge , Qingxiao Tao , Suwen Liu , Ouyang Zhanmu , Yang Yang , Bao Chai , Jingyu Zhang , Man Li , Hongxiang Chen","doi":"10.1016/j.bbi.2025.106218","DOIUrl":"10.1016/j.bbi.2025.106218","url":null,"abstract":"<div><div>Interleukin-17a (IL-17a) has been established as a master regulator of inflammatory cascades in psoriasis pathogenesis. Monoclonal antibodies targeting IL-17a have demonstrated significant efficacy in relieving psoriasis-related symptoms, including the rapid alleviation of chronic itching. However, whether IL-17a is involved in chronic psoriatic pruritus and the specific mechanisms of its action remain poorly understood. In this study, we demonstrate that IL-17a significantly exacerbates chronic itch in a murine model of psoriasis. Mechanistically, IL-17a upregulation in psoriatic skin tissues activated the IL-17a receptor (IL-17Ra) in sensory neurons, subsequently promoting the expression of IL-6 in dorsal root ganglion (DRG) neurons. This neuron-derived IL-6 is transported via sensory nerve fibers to the spinal dorsal horn (SDH), where it triggers astrocyte activation and subsequent IL-1β secretion to potentiates chronic itch signaling in psoriasis. Our findings uncover a neuroimmune circuit in which IL-17a-IL-17Ra signaling on sensory neurons mediates the propagation of pruritic signals from peripheral skin to the central nervous system, with spinal IL-6-astrocyte-IL-1β axis serving as an amplifier of psoriatic pruritus.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106218"},"PeriodicalIF":7.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741056","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 : 2025-12-09DOI: 10.1016/j.bbi.2025.106220
Michael J. Butler , Jade A. Blackwell , Andrew A. Sanchez , Hannah F. Sanders , Dominic W. Kolonay , Jeferson Jantsch , Stephanie M. Muscat , Maria Elisa Caetano-Silva , Akriti Shrestha , Casey Kin Yun Lim , Sabrina E. Mackey-Alfonso , Bryan D. Alvarez , Robert H. McCusker , Jacob M. Allen , Kedryn K. Baskin , Ruth M. Barrientos
Western-style diets, high in saturated fats and refined carbohydrates and low in dietary fiber, are strongly linked to cognitive decline, particularly in aging. However, the specific macronutrient contributions and mechanisms underlying these effects remain unclear. Here, we investigated how short-term exposure to refined-ingredient diets (RDs) varying in fat and sugar content impacts memory, mitochondrial function, and metabolic signaling in young adult and aged male rats. A key finding was that amygdala-dependent memory was broadly impaired in aged rats across all RDs, regardless of fat or sugar content, suggesting a unique vulnerability of the aging amygdala to refined dietary ingredients. In contrast, hippocampal-dependent memory impairments were observed only in aged rats fed a high-fat, low-sugar RD. Functional mitochondrial assays revealed significant RD-induced reductions in oxygen consumption in amygdalar and hippocampal mitochondria isolated from aged rats. Cell-type–specific analyses identified aged microglia as particularly susceptible, showing widespread suppression of mitochondrial respiration with limited metabolic flexibility. Astrocytes and synaptic mitochondria exhibited more region- and age-specific effects. All RDs lacked dietary fiber, and consistent with prior findings, butyrate, a microbial-derived short-chain fatty acid, was rapidly and robustly depleted in both gut and circulation, especially in aged animals. Proteomic and phosphoproteomic analyses identified diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, including complex I subunits and glutamate receptor signaling. Together, these findings reveal that the aged amygdala is especially sensitive to refined diet exposure and highlight microbial, metabolic, and inflammatory pathways that may underlie diet-induced cognitive decline.
{"title":"The aged amygdala’s unique sensitivity to refined diets, independent of fat or sugar content: A brain region and cell type-specific analysis","authors":"Michael J. Butler , Jade A. Blackwell , Andrew A. Sanchez , Hannah F. Sanders , Dominic W. Kolonay , Jeferson Jantsch , Stephanie M. Muscat , Maria Elisa Caetano-Silva , Akriti Shrestha , Casey Kin Yun Lim , Sabrina E. Mackey-Alfonso , Bryan D. Alvarez , Robert H. McCusker , Jacob M. Allen , Kedryn K. Baskin , Ruth M. Barrientos","doi":"10.1016/j.bbi.2025.106220","DOIUrl":"10.1016/j.bbi.2025.106220","url":null,"abstract":"<div><div>Western-style diets, high in saturated fats and refined carbohydrates and low in dietary fiber, are strongly linked to cognitive decline, particularly in aging. However, the specific macronutrient contributions and mechanisms underlying these effects remain unclear. Here, we investigated how short-term exposure to refined-ingredient diets (RDs) varying in fat and sugar content impacts memory, mitochondrial function, and metabolic signaling in young adult and aged male rats. A key finding was that amygdala-dependent memory was broadly impaired in aged rats across all RDs, regardless of fat or sugar content, suggesting a unique vulnerability of the aging amygdala to refined dietary ingredients. In contrast, hippocampal-dependent memory impairments were observed only in aged rats fed a high-fat, low-sugar RD. Functional mitochondrial assays revealed significant RD-induced reductions in oxygen consumption in amygdalar and hippocampal mitochondria isolated from aged rats. Cell-type–specific analyses identified aged microglia as particularly susceptible, showing widespread suppression of mitochondrial respiration with limited metabolic flexibility. Astrocytes and synaptic mitochondria exhibited more region- and age-specific effects. All RDs lacked dietary fiber, and consistent with prior findings, butyrate, a microbial-derived short-chain fatty acid, was rapidly and robustly depleted in both gut and circulation, especially in aged animals. Proteomic and phosphoproteomic analyses identified diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, including complex I subunits and glutamate receptor signaling. Together, these findings reveal that the aged amygdala is especially sensitive to refined diet exposure and highlight microbial, metabolic, and inflammatory pathways that may underlie diet-induced cognitive decline.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106220"},"PeriodicalIF":7.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741122","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 : 2025-12-09DOI: 10.1016/j.bbi.2025.106215
Yu Guo , Xiaochuan Qi , Ao Wang , Tingting Zhan , Kexin Duan , Wenjie Ma , Changqing Liu
Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and striatum, which accompanied by the activation of NLRP3 inflammasome, autophagic dysfunction and motor disorders. USP9X, as a highly conserved ubiquitin-specific protease, which abnormal expression is closely correlated with various neurodegenerative diseases and neurodevelopmental disorders. However, whether USP9X can regulate the activation of NLRP3 inflammasome in Parkinson’s disease (PD) has not been elucidated yet. In this study, LPS was intraperitoneally injected into wild-type mice to simulate neuroinflammation of Parkinson’s disease and USP9X-shRNA was stereotactic injected into bilateral lateral ventricles (LV) of the mice brain to inhibit the expression of USP9X. The results showed that inhibition of USP9X expression could siginificantly improve the motor dysfunction, activation of NLRP3 inflammasome, degeneration of dopaminergic neurons and activation of microglia induced by LPS. Additionally, the parkin+/− mice exhibited great activation of the NLRP3 inflammasome, loss of dopaminergic neurons and motor dysfunction at an early age. However, downregulation of USP9X expression in parkin+/− mice also significantly improved the activation of the NLRP3 inflammasome, damage to dopaminergic neurons, autophagic dysfunction and motor dysfunction. Therefore, USP9X can be utilized as an effective potential target for inhibiting NLRP3 inflammasomes activation and activating the autophagic function, which expected to be a potential therapeutic strategy for Parkinson’s disease.
{"title":"USP9X suppression attenuates NLRP3 inflammasome activation and ameliorates neuroinflammatory phenotypes with motor function recovery in murine models","authors":"Yu Guo , Xiaochuan Qi , Ao Wang , Tingting Zhan , Kexin Duan , Wenjie Ma , Changqing Liu","doi":"10.1016/j.bbi.2025.106215","DOIUrl":"10.1016/j.bbi.2025.106215","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and striatum, which accompanied by the activation of NLRP3 inflammasome, autophagic dysfunction and motor disorders. USP9X, as a highly conserved ubiquitin-specific protease, which abnormal expression is closely correlated with various neurodegenerative diseases and neurodevelopmental disorders. However, whether USP9X can regulate the activation of NLRP3 inflammasome in Parkinson’s disease (PD) has not been elucidated yet. In this study, LPS was intraperitoneally injected into wild-type mice to simulate neuroinflammation of Parkinson’s disease and USP9X-shRNA was stereotactic injected into bilateral lateral ventricles (LV) of the mice brain to inhibit the expression of USP9X. The results showed that inhibition of USP9X expression could siginificantly improve the motor dysfunction, activation of NLRP3 inflammasome, degeneration of dopaminergic neurons and activation of microglia induced by LPS. Additionally, the parkin<sup>+/−</sup> mice exhibited great activation of the NLRP3 inflammasome, loss of dopaminergic neurons and motor dysfunction at an early age. However, downregulation of USP9X expression in parkin<sup>+/−</sup> mice also significantly improved the activation of the NLRP3 inflammasome, damage to dopaminergic neurons, autophagic dysfunction and motor dysfunction. Therefore, USP9X can be utilized as an effective potential target for inhibiting NLRP3 inflammasomes activation and activating the autophagic function, which expected to be a potential therapeutic strategy for Parkinson’s disease.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106215"},"PeriodicalIF":7.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741067","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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