Pub Date : 2025-12-19DOI: 10.1016/j.bbi.2025.106230
Gabrielle R. Rinne , Christine Dunkel Schetter , Susan Jackman , Steve W. Cole
The in-utero environment shapes offspring mental and physical health trajectories over the lifespan, likely through developmental adaptations to fetal biological systems. Offspring immune system development is a putative pathway through which the prenatal environment influences offspring health. The current study tested associations of maternal prenatal depressive and anxiety symptoms with infant pro-inflammatory and antiviral gene expression in a sample of 118 mother-infant pairs enrolled in a longitudinal study. Mothers reported on depressive and anxiety symptoms during interviews in early, mid, and late pregnancy. About one month after birth, trained research staff collected dried blood spots from infants during a heel stick procedure (M = 1.3 months, SD = 1.1 months). Infant dried blood spots were assayed for genome-wide transcriptional profiles using RNAseq. We evaluated associations of maternal prenatal depressive and anxiety symptoms with infant genome-wide transcriptional profiles and used bioinformatics analyses to identify upstream transcriptional pathways of differentially expressed genes. Higher maternal depressive symptom levels over the course of pregnancy were associated with upregulation of the pro-inflammatory NF-κB transcription control pathway and downregulation of the antiviral IRF control pathway in infants. In contrast, anxiety symptoms were associated with downregulation of the antiviral transcriptional control pathway in infants but were not associated with differences in the pro-inflammatory transcriptional control pathway. However, the association of anxiety symptoms with antiviral transcriptional control pathways was no longer significant with adjustment for depressive symptoms. These findings suggest that depressive symptoms during pregnancy may influence infant immune function via inflammatory and antiviral transcriptional control pathways, with potential implications for subsequent health.
{"title":"Developmental origins of immune function: Maternal prenatal mood is associated with infant immune cell gene expression","authors":"Gabrielle R. Rinne , Christine Dunkel Schetter , Susan Jackman , Steve W. Cole","doi":"10.1016/j.bbi.2025.106230","DOIUrl":"10.1016/j.bbi.2025.106230","url":null,"abstract":"<div><div>The in-utero environment shapes offspring mental and physical health trajectories over the lifespan, likely through developmental adaptations to fetal biological systems. Offspring immune system development is a putative pathway through which the prenatal environment influences offspring health. The current study tested associations of maternal prenatal depressive and anxiety symptoms with infant pro-inflammatory and antiviral gene expression in a sample of 118 mother-infant pairs enrolled in a longitudinal study. Mothers reported on depressive and anxiety symptoms during interviews in early, mid, and late pregnancy. About one month after birth, trained research staff collected dried blood spots from infants during a heel stick procedure (<em>M</em> = 1.3 months, <em>SD</em> = 1.1 months). Infant dried blood spots were assayed for genome-wide transcriptional profiles using RNAseq. We evaluated associations of maternal prenatal depressive and anxiety symptoms with infant genome-wide transcriptional profiles and used bioinformatics analyses to identify upstream transcriptional pathways of differentially expressed genes. Higher maternal depressive symptom levels over the course of pregnancy were associated with upregulation of the pro-inflammatory NF-κB transcription control pathway and downregulation of the antiviral IRF control pathway in infants. In contrast, anxiety symptoms were associated with downregulation of the antiviral transcriptional control pathway in infants but were not associated with differences in the pro-inflammatory transcriptional control pathway. However, the association of anxiety symptoms with antiviral transcriptional control pathways was no longer significant with adjustment for depressive symptoms. These findings suggest that depressive symptoms during pregnancy may influence infant immune function via inflammatory and antiviral transcriptional control pathways, with potential implications for subsequent health.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106230"},"PeriodicalIF":7.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803186","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 : 2025-12-19DOI: 10.1016/j.bbi.2025.106234
Magdalena Widziolek , Anna Mieszkowska , Magdalena Marcinkowska , Aleksandra Domagalska , Maria Zawisza , Zbigniew Soltys , Jan Potempa , Magdalena Chadzinska
Porphyromonas gingivalis (Pg), a keystone pathogen in the development of periodontitis, has been implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). The gingipains, Pg crucial virulence factors, have been detected in the brains of AD patients and suggested to be involved in neuroinflammation, which leads to neuronal death. However, the mechanisms underlying Pg brain invasion and its inflammatory effect remain poorly understood.
In this study, using a zebrafish larval model, we investigated the gingipain-dependent effects of systemic and local hindbrain infection with Pg, on: (i) neuroinflammation and cell death, (ii) Pg phagocytosis and persistence in the brain, (iii) activation of microglia/macrophages, (iv) cerebral vasculature integrity, and (v) larval behavioural changes.
Systemic infection with wild-type Pg W83, but not with the gingipain-null mutant (ΔK/R-ab), resulted in increased bacterial survival in the brain and upregulation of the expression of pro-inflammatory genes both in the brain and periphery. Furthermore, Pg W83 also induced microglia/macrophages activation, as indicated by morphological changes and upregulation of activation marker expression, however number of microglia was reduced upon Pg W83 systemic infection. Finally, alterations in cerebral vasculature and larval locomotor activity were also observed.
In contrast, the ΔK/R-ab mutant was rapidly cleared and did not induce inflammatory responses, underscoring the pivotal role of gingipains in Pg survival, microglia activation and neuroinflammation.
Interestingly, the direct hindbrain inoculation of Pg induced only a mild, transient inflammation, indicating that systemic dissemination and potentially peripheral inflammation is crucial in the affecting blood–brain barrier and neuroinflammation. In contrast to systemic infection, local infection with Pg W83 or injection of purified gingipains led to increased microglia/macrophages numbers but similarly to systemically administered bacteria, Pg W83 was more effective in activating the microglia/macrophages than the ΔK/R-ab mutant, which was rapidly phagocytosed and cleared. Moreover, during local infection Pg W83, but not ΔK/R-ab, was able to induce cell death in the brains of infected larvae.
Collectively, these findings highlight the gingipain-dependent mechanisms of Pg-induced neuroinflammation and emphasize the importance of further investigation into the role of the oral-brain axis in neurodegenerative diseases. In addition, this study highlights the utility of zebrafish larvae as a powerful tool to investigate host immunity-pathogen interactions in the brain.
{"title":"Porphyromonas gingivalis induces neuroinflammation in a gingipain-dependent manner in zebrafish larvae","authors":"Magdalena Widziolek , Anna Mieszkowska , Magdalena Marcinkowska , Aleksandra Domagalska , Maria Zawisza , Zbigniew Soltys , Jan Potempa , Magdalena Chadzinska","doi":"10.1016/j.bbi.2025.106234","DOIUrl":"10.1016/j.bbi.2025.106234","url":null,"abstract":"<div><div><em>Porphyromonas gingivalis</em> (<em>Pg</em>), a keystone pathogen in the development of periodontitis, has been implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). The gingipains, <em>Pg</em> crucial virulence factors, have been detected in the brains of AD patients and suggested to be involved in neuroinflammation, which leads to neuronal death. However, the mechanisms underlying <em>Pg</em> brain invasion and its inflammatory effect remain poorly understood.</div><div>In this study, using a zebrafish larval model, we investigated the gingipain-dependent effects of systemic and local hindbrain infection with <em>Pg</em>, on: <em>(i)</em> neuroinflammation and cell death, <em>(ii) Pg</em> phagocytosis and persistence in the brain, <em>(iii)</em> activation of microglia/macrophages, <em>(iv)</em> cerebral vasculature integrity, and <em>(v)</em> larval behavioural changes.</div><div>Systemic infection with wild-type <em>Pg</em> W83, but not with the gingipain-null mutant (<em>ΔK/R-ab</em>), resulted in increased bacterial survival in the brain and upregulation of the expression of pro-inflammatory genes both in the brain and periphery. Furthermore, <em>Pg</em> W83 also induced microglia/macrophages activation, as indicated by morphological changes and upregulation of activation marker expression, however number of microglia was reduced upon <em>Pg</em> W83 systemic infection. Finally, alterations in cerebral vasculature and larval locomotor activity were also observed.</div><div>In contrast, the <em>ΔK/R-ab</em> mutant was rapidly cleared and did not induce inflammatory responses, underscoring the pivotal role of gingipains in <em>Pg</em> survival, microglia activation and neuroinflammation.</div><div>Interestingly, the direct hindbrain inoculation of <em>Pg</em> induced only a mild, transient inflammation, indicating that systemic dissemination and potentially peripheral inflammation is crucial in the affecting blood–brain barrier and neuroinflammation. In contrast to systemic infection, local infection with <em>Pg</em> W83 or injection of purified gingipains led to increased microglia/macrophages numbers but similarly to systemically administered bacteria, <em>Pg</em> W83 was more effective in activating the microglia/macrophages than the <em>ΔK/R-ab</em> mutant, which was rapidly phagocytosed and cleared. Moreover, during local infection <em>Pg</em> W83, but not <em>ΔK/R-ab,</em> was able to induce cell death in the brains of infected larvae.</div><div>Collectively, these findings highlight the gingipain-dependent mechanisms of <em>Pg</em>-induced neuroinflammation and emphasize the importance of further investigation into the role of the oral-brain axis in neurodegenerative diseases. In addition, this study highlights the utility of zebrafish larvae as a powerful tool to investigate host immunity-pathogen interactions in the brain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106234"},"PeriodicalIF":7.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803159","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.2025.106225
Saül Pascual-Diaz , Maria Suñol , Marie-Eve Hoeppli , Emma Biggs , Christopher D. King , Nima Aghaeepour , Martin S. Angst , Edward Ganio , Amelie Cambriel , Dorien Feyaerts , Brice Gaudilliere , Jennifer N. Stinson , Massieh Moayedi , Robert C. Coghill , Laura E. Simons , Marina López-Solà
Chronic musculoskeletal (MSK) pain affects a substantial proportion of youth, with 5 % reporting high-impact symptoms. Chronic pain in youth leads to multifaceted negative consequences that profoundly affect adolescents’ quality of life (QoL) and future outcomes. Recent studies suggest that neuro-immune interactions significantly contribute to chronic pain. However, how systemic immune dysregulation influences brain function, and how these brain changes affect well-being and functioning in chronic pain remains unclear. This study aims to examine the convergence between immune function and brain processing during a multisensory task to identify novel mechanistic pathways that may explain reduced QoL in adolescents with chronic MSK pain (N = 129). We used a multisensory fMRI task designed to mimic the unpleasant sensory experiences that adolescents and adults with chronic pain often encounter in daily life. Higher task-evoked activation in the rostral anterior cingulate and dorsomedial prefrontal cortices (rACC–dmPFC), which support threat appraisal and response regulation, was associated with lower physical QoL (pFWE = 0.005). Lower physical QoL was also associated with augmented functional connectivity between the rACC-dmPFC region and sensory processing areas in the somatosensory (pFWE = 0.002) and visual (pFWE = 0.049) cortices. Higher systemic pro-inflammatory activity in immature neutrophils was also associated with lower physical QoL (p = 0.01). Furthermore, task-evoked brain activation in the rACC-dmPFC partially mediated the relationship between neutrophil-mediated inflammatory responses and reduced physical QoL. These findings suggest a potential neuro-immune pathway through which systemic immune alterations may affect brain function and QoL in adolescents with chronic MSK pain.
{"title":"Brain-immune correlates of quality of life in adolescents with chronic musculoskeletal pain","authors":"Saül Pascual-Diaz , Maria Suñol , Marie-Eve Hoeppli , Emma Biggs , Christopher D. King , Nima Aghaeepour , Martin S. Angst , Edward Ganio , Amelie Cambriel , Dorien Feyaerts , Brice Gaudilliere , Jennifer N. Stinson , Massieh Moayedi , Robert C. Coghill , Laura E. Simons , Marina López-Solà","doi":"10.1016/j.bbi.2025.106225","DOIUrl":"10.1016/j.bbi.2025.106225","url":null,"abstract":"<div><div>Chronic musculoskeletal (MSK) pain affects a substantial proportion of youth, with 5 % reporting high-impact symptoms. Chronic pain in youth leads to multifaceted negative consequences that profoundly affect adolescents’ quality of life (QoL) and future outcomes. Recent studies suggest that neuro-immune interactions significantly contribute to chronic pain. However, how systemic immune dysregulation influences brain function, and how these brain changes affect well-being and functioning in chronic pain remains unclear. This study aims to examine the convergence between immune function and brain processing during a multisensory task to identify novel mechanistic pathways that may explain reduced QoL in adolescents with chronic MSK pain (N = 129). We used a multisensory fMRI task designed to mimic the unpleasant sensory experiences that adolescents and adults with chronic pain often encounter in daily life. Higher task-evoked activation in the rostral anterior cingulate and dorsomedial prefrontal cortices (rACC–dmPFC), which support threat appraisal and response regulation, was associated with lower physical QoL (pFWE = 0.005). Lower physical QoL was also associated with augmented functional connectivity between the rACC-dmPFC region and sensory processing areas in the somatosensory (pFWE = 0.002) and visual (pFWE = 0.049) cortices. Higher systemic pro-inflammatory activity in immature neutrophils was also associated with lower physical QoL (p = 0.01). Furthermore, task-evoked brain activation in the rACC-dmPFC partially mediated the relationship between neutrophil-mediated inflammatory responses and reduced physical QoL. These findings suggest a potential neuro-immune pathway through which systemic immune alterations may affect brain function and QoL in adolescents with chronic MSK pain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106225"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797426","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.2025.106224
Yoel Shor , Reut Said , Nina Fainstein , Gilly Wolf , Lihi Sofer Stepanov , Marva Lachish , Tal Ganz , Yara Shwaiky , Hadar Benyamini , Yuval Nevo , Yarden Brock , Jonathan Gurevitz , Tzuri Lifschytz , Amit Lotan , Tamir Ben-Hur
Background
Core pathology in Alzheimer’s disease (AD) includes amyloid-β (Aβ) deposition, gliosis, and eventual neuronal loss. Depression during midlife increases the risk of developing AD at late life. Late-life depression is highly prevalent among AD patients, but its role in AD pathogenesis is unclear, and specifically whether it pushes the brain with established AD pathology towards degeneration. CNS myeloid cells (Microglia and CNS-associated macrophages) clear Aβ early on; however, in advanced disease stages, they adopt a neurotoxic phenotype that exacerbates neurodegeneration. It is unclear whether and how stress and depression influence CNS myeloid cells’ dysfunction in AD and the neurodegenerative process.
Methods
To investigate the impact of chronic stress on microglial function and on neurodegeneration, we utilized the 5xFAD mouse model, which exhibits extensive Aβ pathology but no neuronal loss at age 7 months, representing a late preclinical AD stage. We used a six-week chronic mild stress (CMS) paradigm to induce depressive behavior, after which CNS myeloid cell activation state was evaluated by transcriptomic analysis, activation marker expression and oxidation function. Neuronal and microglial densities were assessed histologically.
Results
Transcriptomic analysis of freshly isolated CNS myeloid cells showed a basal hyper-activated state in non-stressed 5xFAD mice, whereas CMS suppressed multiple immunologic and metabolic pathways. CMS reduced CD68 expression and reduced oxidative function in CNS myeloid cells. CMS did not induce neurodegeneration in the (behaviorally-relevant) pre-frontal, primary motor, hippocampal and Amygdalar cortices in 5xFAD mice. Rather, CMS protected these regions from microglia-mediated neurodegeneration, caused by a microbial TLR2 agonist.
Conclusion
Chronic stress and depression attenuate CNS myeloid cells. While this has been shown to promote amyloid pathology at early stages, similar attenuation of CNS myeloid cells at the stage of established AD pathology may interfere with their transition into fully neurotoxic microglia, which cause neurodegeneration. These findings highlight the importance of tailoring microglial-targeted therapies to the stage-dependent roles of these cells during AD progression.
{"title":"The paradoxical protective effect of chronic stress on advanced Alzheimer’s disease pathology","authors":"Yoel Shor , Reut Said , Nina Fainstein , Gilly Wolf , Lihi Sofer Stepanov , Marva Lachish , Tal Ganz , Yara Shwaiky , Hadar Benyamini , Yuval Nevo , Yarden Brock , Jonathan Gurevitz , Tzuri Lifschytz , Amit Lotan , Tamir Ben-Hur","doi":"10.1016/j.bbi.2025.106224","DOIUrl":"10.1016/j.bbi.2025.106224","url":null,"abstract":"<div><h3>Background</h3><div>Core pathology in Alzheimer’s disease (AD) includes amyloid-β (Aβ) deposition, gliosis, and eventual neuronal loss. Depression during midlife increases the risk of developing AD at late life. Late-life depression is highly prevalent among AD patients, but its role in AD pathogenesis is unclear, and specifically whether it pushes the brain with established AD pathology towards degeneration. CNS myeloid cells (Microglia and CNS-associated macrophages) clear Aβ early on; however, in advanced disease stages, they adopt a neurotoxic phenotype that exacerbates neurodegeneration. It is unclear whether and how stress and depression influence CNS myeloid cells’ dysfunction in AD and the neurodegenerative process.</div></div><div><h3>Methods</h3><div>To investigate the impact of chronic stress on microglial function and on neurodegeneration, we utilized the 5xFAD mouse model, which exhibits extensive Aβ pathology but no neuronal loss at age 7 months, representing a late preclinical AD stage. We used a six-week chronic mild stress (CMS) paradigm to induce depressive behavior, after which CNS myeloid cell activation state was evaluated by transcriptomic analysis, activation marker expression and oxidation function. Neuronal and microglial densities were assessed histologically.</div></div><div><h3>Results</h3><div>Transcriptomic analysis of freshly isolated CNS myeloid cells showed a basal hyper-activated state in non-stressed 5xFAD mice, whereas CMS suppressed multiple immunologic and metabolic pathways. CMS reduced CD68 expression and reduced oxidative function in CNS myeloid cells. CMS did not induce neurodegeneration in the (behaviorally-relevant) pre-frontal, primary motor, hippocampal and Amygdalar cortices in 5xFAD mice. Rather, CMS protected these regions from microglia-mediated neurodegeneration, caused by a microbial TLR2 agonist.</div></div><div><h3>Conclusion</h3><div>Chronic stress and depression attenuate CNS myeloid cells. While this has been shown to promote amyloid pathology at early stages, similar attenuation of CNS myeloid cells at the stage of established AD pathology may interfere with their transition into fully neurotoxic microglia, which cause neurodegeneration. These findings highlight the importance of tailoring microglial-targeted therapies to the stage-dependent roles of these cells during AD progression.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106224"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800391","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.2025.106233
Michael R. Duggan , Zena K. Chatila , Lavinia A. Auber , Esther Silberberg , Juan R. Fernandez , Keenan A. Walker , Nikki M. Schultek
Investments in SARS-CoV-2 research provide a unique opportunity to explore how microbes may contribute to neurological conditions, an area of investigation that has been chronically underfunded. As exemplified by HIV/AIDS funding, crisis-driven research can yield broader biomedical advances, including spillover effects that address unanticipated and unmet medical needs. Leveraging newly established SARS-CoV-2 funding opportunities to study immune crosstalk and genetic predispositions could reveal therapeutic pathways and biomarkers for individuals who are vulnerable to infection-related dementia risk and neuropsychiatric symptoms. Despite the vast consequences of SARS-CoV-2, research investments following this pandemic may have long lasting benefits for other scientific endeavors, including insights for microbial contributions to neurodegenerative disease.
{"title":"Can the COVID-19 pandemic advance neuroinfectious research?","authors":"Michael R. Duggan , Zena K. Chatila , Lavinia A. Auber , Esther Silberberg , Juan R. Fernandez , Keenan A. Walker , Nikki M. Schultek","doi":"10.1016/j.bbi.2025.106233","DOIUrl":"10.1016/j.bbi.2025.106233","url":null,"abstract":"<div><div>Investments in SARS-CoV-2 research provide a unique opportunity to explore how microbes may contribute to neurological conditions, an area of investigation that has been chronically underfunded. As exemplified by HIV/AIDS funding, crisis-driven research can yield broader biomedical advances, including spillover effects that address unanticipated and unmet medical needs. Leveraging newly established SARS-CoV-2 funding opportunities to study immune crosstalk and genetic predispositions could reveal therapeutic pathways and biomarkers for individuals who are vulnerable to infection-related dementia risk and neuropsychiatric symptoms. Despite the vast consequences of SARS-CoV-2, research investments following this pandemic may have long lasting benefits for other scientific endeavors, including insights for microbial contributions to neurodegenerative disease.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106233"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797460","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.2025.106228
Sarah E. Fromme , Gara Arteaga-Henríquez , Bartholomeus C.M. Haarman , Annemarie Wijkhuijs , Raf Berghmans , Trine Munk-Olsen , Hemmo Drexhage , Bernhard T. Baune
<div><div>A proportion of patients diagnosed with major depressive disorder (MDD) exhibit signs of premature T cell aging, i.e. memory T cell inflation, characterized by elevated levels of memory CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Physical endurance training, including spinning therapy (ST), is known to counteract both T cell aging and depression.</div><div>The primary aim of this randomized, treatment-as-usual (TAU)-controlled study was to investigate whether signs of T cell aging (determined prior to ST) characterized remitters and responders to the intervention.</div><div>Patients aged 18–65 years with a diagnosis of MDD (Hamilton Depression Rating Scale (HDRS) ≥ 13) were included and randomized 1:1 to TAU or TAU + ST. The intervention consisted of moderate-intensity cycling sessions (30 min, three times per week), for eight consecutive weeks. A total of 72 patients (n = 35 TAU, n = 37 TAU + ST) with complete baseline immunophenotyping were included in the analyses (49 % females; mean age, 32 years).</div><div>We found that remitters to TAU + ST displayed significantly higher baseline levels of CD8<sup>+</sup> memory T cells, particularly T central memory (Tcm) cells and T effector memory cells re-expressing CD45RA (TEMRA) cells, compared to non-remitters. Correction for potential confounders and logistic regression analysis revealed that baseline levels of CD8<sup>+</sup> Tcm cells showed the strongest predictive value in the TAU + ST group (OR = 7.66, <em>P</em> = 0.03), suggesting that these cells may serve as treatment-specific predictors of remission to adjunctive ST. Post hoc stratification of patients based on the levels of CD8<sup>+</sup>Tcm cells identified a subgroup of n = 20 patients exhibiting several signs of T cell inflation in both the CD8<sup>+</sup> and CD4<sup>+</sup> T memory cell populations. This subgroup was older and showed a higher prevalence of cytomegalovirus seropositivity, suggesting a state of post-infectious T cell senescence. In addition, this subgroup was characterized by higher remission rates to TAU + ST compared to TAU alone, particularly in the long run (i.e., 75 % vs. 42 % at week 8, and 75 % vs. 17 % at the end of the follow-up phase at week 24, <em>P</em> = 0.03; note the small group sizes of n = 8 and n = 12 patients, respectively). Although no significant effects of add-on ST on CD8<sup>+</sup> memory T cells were found, adjunctive ST significantly increased naïve CD4<sup>+</sup> T cells and decreased effector memory CD4<sup>+</sup> T cells within the senescent subgroup. Add-on ST was not superior to TAU in the entire group of patients with MDD.</div><div>Taken together, our findings suggest that patients with MDD with a T memory cell inflation profile may be the one and only who would benefit from TAU + ST as an add-on treatment strategy. These results support the development of personalized psychiatry approaches guided by immunological profiling and challenge the conventional “one-size-fit”
{"title":"One treatment does not fit all: Indications that spinning therapy benefits only a subgroup of patients with depression characterized by a T memory cell inflation profile","authors":"Sarah E. Fromme , Gara Arteaga-Henríquez , Bartholomeus C.M. Haarman , Annemarie Wijkhuijs , Raf Berghmans , Trine Munk-Olsen , Hemmo Drexhage , Bernhard T. Baune","doi":"10.1016/j.bbi.2025.106228","DOIUrl":"10.1016/j.bbi.2025.106228","url":null,"abstract":"<div><div>A proportion of patients diagnosed with major depressive disorder (MDD) exhibit signs of premature T cell aging, i.e. memory T cell inflation, characterized by elevated levels of memory CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Physical endurance training, including spinning therapy (ST), is known to counteract both T cell aging and depression.</div><div>The primary aim of this randomized, treatment-as-usual (TAU)-controlled study was to investigate whether signs of T cell aging (determined prior to ST) characterized remitters and responders to the intervention.</div><div>Patients aged 18–65 years with a diagnosis of MDD (Hamilton Depression Rating Scale (HDRS) ≥ 13) were included and randomized 1:1 to TAU or TAU + ST. The intervention consisted of moderate-intensity cycling sessions (30 min, three times per week), for eight consecutive weeks. A total of 72 patients (n = 35 TAU, n = 37 TAU + ST) with complete baseline immunophenotyping were included in the analyses (49 % females; mean age, 32 years).</div><div>We found that remitters to TAU + ST displayed significantly higher baseline levels of CD8<sup>+</sup> memory T cells, particularly T central memory (Tcm) cells and T effector memory cells re-expressing CD45RA (TEMRA) cells, compared to non-remitters. Correction for potential confounders and logistic regression analysis revealed that baseline levels of CD8<sup>+</sup> Tcm cells showed the strongest predictive value in the TAU + ST group (OR = 7.66, <em>P</em> = 0.03), suggesting that these cells may serve as treatment-specific predictors of remission to adjunctive ST. Post hoc stratification of patients based on the levels of CD8<sup>+</sup>Tcm cells identified a subgroup of n = 20 patients exhibiting several signs of T cell inflation in both the CD8<sup>+</sup> and CD4<sup>+</sup> T memory cell populations. This subgroup was older and showed a higher prevalence of cytomegalovirus seropositivity, suggesting a state of post-infectious T cell senescence. In addition, this subgroup was characterized by higher remission rates to TAU + ST compared to TAU alone, particularly in the long run (i.e., 75 % vs. 42 % at week 8, and 75 % vs. 17 % at the end of the follow-up phase at week 24, <em>P</em> = 0.03; note the small group sizes of n = 8 and n = 12 patients, respectively). Although no significant effects of add-on ST on CD8<sup>+</sup> memory T cells were found, adjunctive ST significantly increased naïve CD4<sup>+</sup> T cells and decreased effector memory CD4<sup>+</sup> T cells within the senescent subgroup. Add-on ST was not superior to TAU in the entire group of patients with MDD.</div><div>Taken together, our findings suggest that patients with MDD with a T memory cell inflation profile may be the one and only who would benefit from TAU + ST as an add-on treatment strategy. These results support the development of personalized psychiatry approaches guided by immunological profiling and challenge the conventional “one-size-fit”","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106228"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800330","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.2025.106229
Florencia Peña , Claudio Rodríguez-Camejo , Ana Hernández , Mayda Rivas , Anderson Saravia , Diego Serantes , Juan Pedro Castro , Pablo Torterolo , Teresa Freire , Luciana Benedetto
Background
sleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation.
Methods
mother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups.
Results
maternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 ± 734 µg/mL) compared with the control group (8666 ± 463 µg/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 ± 0.58) and male (3.81 ± 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 ± 0.25, p = 0.004; males: 2.44 ± 0.25; p = 0.029).
Conclusions
Chronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with certain effects observed only in male pups.
{"title":"Differential effects of postpartum sleep restriction on maternal and offspring immunity in the rat","authors":"Florencia Peña , Claudio Rodríguez-Camejo , Ana Hernández , Mayda Rivas , Anderson Saravia , Diego Serantes , Juan Pedro Castro , Pablo Torterolo , Teresa Freire , Luciana Benedetto","doi":"10.1016/j.bbi.2025.106229","DOIUrl":"10.1016/j.bbi.2025.106229","url":null,"abstract":"<div><h3>Background</h3><div>sleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation.</div></div><div><h3>Methods</h3><div>mother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups.</div></div><div><h3>Results</h3><div>maternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 ± 734 µg/mL) compared with the control group (8666 ± 463 µg/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 ± 0.58) and male (3.81 ± 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 ± 0.25, p = 0.004; males: 2.44 ± 0.25; p = 0.029).</div></div><div><h3>Conclusions</h3><div>Chronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with certain effects observed only in male pups.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106229"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800408","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.2025.106227
Michal Bajo , Pauravi Gandhi , Suzanne S. Fei , Yun Yu , Lina Gao , Rupak Khadka , Madison B. Blanton , Ilhem Messaoudi , Anna S. Warden , R. Dayne Mayfield , Verginia C. Cuzon Carlson , Kathleen A. Grant , Marisa Roberto
The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Understanding how chronic alcohol dysregulates inflammatory pathways in the brain leading to altered neuronal functions could provide insight into specific mechanisms and neuroadaptations that may contribute to drinking behaviors. For example, the neuroadaptations at inhibitory GABAergic synapses in the central nucleus of the amygdala (CeA) of rodents and macaques involve the recruitment of neuroimmune pathways. This study tested the hypothesis that chronic alcohol consumption dysregulates the pro-inflammatory cytokine, interleukin 6 (IL-6) in the CeA of rhesus macaques. Male and female rhesus macaques were provided continuous choice to drink either 4 % (w/v) ethanol or water for 22 h/day, every day, for more than one year. We assessed the impact of chronic ethanol drinking on the cytokine abundance, including IL-6, in the blood, and adaptive changes in the CeA GABAergic transmission and transcriptome. We observed a main effect of sex on the IL-6 circulating plasma levels at necropsy, with higher IL-6 plasma levels in females, but no main effect of ethanol nor an interaction between sex and ethanol drinking. IL-6 decreased CeA GABA release (sIPSC frequency) in both control and alcohol drinkers, however chronic ethanol drinking significantly potentiated the IL-6 effects in both sexes. While, IL-6 had no effects on the sIPSC amplitudes in the control group, we observed a main effect of ethanol drinking on IL-6-induced decrease of sIPSC amplitude in both male and female drinkers. IL-6 also significantly prolonged the kinetics (decay times) of sIPSCs in male controls and drinkers, but not in the females, regardless of drinking. These data suggest that IL-6 modulation of GABAergic transmission within the CeA via a presynaptic reduction in GABA release independent of sex, whereas postsynaptic GABA receptor mediated functions (sIPSC amplitude and decay time) show sex- and ethanol specific effects. Lastly, transcriptomic analysis of the IL-6-immune-related genes in the CeA between high and low ethanol drinkers identified several DEGs (differentially expressed genes) implicating the neural and glial processes, and extracellular matrix as a generalized inflammatory response to ethanol in the high drinkers.
{"title":"Chronic alcohol consumption sex-dependently affects IL-6 modulation of GABAergic synapses in the central amygdala of rhesus macaques","authors":"Michal Bajo , Pauravi Gandhi , Suzanne S. Fei , Yun Yu , Lina Gao , Rupak Khadka , Madison B. Blanton , Ilhem Messaoudi , Anna S. Warden , R. Dayne Mayfield , Verginia C. Cuzon Carlson , Kathleen A. Grant , Marisa Roberto","doi":"10.1016/j.bbi.2025.106227","DOIUrl":"10.1016/j.bbi.2025.106227","url":null,"abstract":"<div><div>The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Understanding how chronic alcohol dysregulates inflammatory pathways in the brain leading to altered neuronal functions could provide insight into specific mechanisms and neuroadaptations that may contribute to drinking behaviors. For example, the neuroadaptations at inhibitory GABAergic synapses in the central nucleus of the amygdala (CeA) of rodents and macaques involve the recruitment of neuroimmune pathways. This study tested the hypothesis that chronic alcohol consumption dysregulates the pro-inflammatory cytokine, interleukin 6 (IL-6) in the CeA of rhesus macaques. Male and female rhesus macaques were provided continuous choice to drink either 4 % (w/v) ethanol or water for 22 h/day, every day, for more than one year. We assessed the impact of chronic ethanol drinking on the cytokine abundance, including IL-6, in the blood, and adaptive changes in the CeA GABAergic transmission and transcriptome. We observed a main effect of sex on the IL-6 circulating plasma levels at necropsy, with higher IL-6 plasma levels in females, but no main effect of ethanol nor an interaction between sex and ethanol drinking. IL-6 decreased CeA GABA release (sIPSC frequency) in both control and alcohol drinkers, however chronic ethanol drinking significantly potentiated the IL-6 effects in both sexes. While, IL-6 had no effects on the sIPSC amplitudes in the control group, we observed a main effect of ethanol drinking on IL-6-induced decrease of sIPSC amplitude in both male and female drinkers. IL-6 also significantly prolonged the kinetics (decay times) of sIPSCs in male controls and drinkers, but not in the females, regardless of drinking. These data suggest that IL-6 modulation of GABAergic transmission within the CeA via a presynaptic reduction in GABA release independent of sex, whereas postsynaptic GABA receptor mediated functions (sIPSC amplitude and decay time) show sex- and ethanol specific effects. Lastly, transcriptomic analysis of the IL-6-immune-related genes in the CeA between high and low ethanol drinkers identified several DEGs (differentially expressed genes) implicating the neural and glial processes, and extracellular matrix as a generalized inflammatory response to ethanol in the high drinkers.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106227"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800259","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.2025.106223
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}
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