Brain, Behavior, and Immunity最新文献

{"title":"HDAC inhibitors engage MITF and the disease-associated microglia signature to enhance amyloid β uptake","authors":"Verena Haage ,&nbsp;John F. Tuddenham ,&nbsp;Alex Bautista ,&nbsp;Frankie Garcia G. ,&nbsp;Charles C. White ,&nbsp;Ronak Patel ,&nbsp;Natacha Comandante-Lou ,&nbsp;Victoria Marshe ,&nbsp;Jennifer Griffin ,&nbsp;Ye Zhou ,&nbsp;Deniz Ghaffari ,&nbsp;Beatrice Acheson ,&nbsp;Mariko Taga ,&nbsp;Peter H. St George-Hyslop ,&nbsp;Rajesh Kumar Soni ,&nbsp;Peter A. Sims ,&nbsp;Vilas Menon ,&nbsp;Andrew A. Sproul ,&nbsp;Philip L. De Jager","doi":"10.1016/j.bbi.2025.05.027","DOIUrl":"10.1016/j.bbi.2025.05.027","url":null,"abstract":"<div><div>Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2dependent state termed DAM2, with each state being characterized by the expression of specific marker genes (Keren-Shaul, 2017). Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAM in humans (Pettas, 2022; Jauregui, 2023; Friedman, 2018; Mathys, 2019; Tuddenham, 2024); however, whether DAM play beneficial or detrimental roles in the context of neurodegeneration is still under debate (Butovsky and Weiner, 2018; Wang and Colonna, 2019). Here, we present a pharmacological approach to mimic human DAM <em>in vitro</em>: we validated <em>in silico</em> predictions that two different histone deacetylase (HDAC) inhibitors, Entinostat and Vorinostat, recapitulate aspects of the DAM signature in two human microglia-like model systems. HDAC inhibition increases RNA expression of <em>MITF</em>, a transcription factor previously described as a regulator of the DAM signature (Dolan, 2023). This engagement of <em>MITF</em> appears to be associated with one part of the DAM signature, refining our understanding of the DAM signature as a combination of at least two transcriptional programs that appear to be correlated <em>in vivo</em>. Further, we functionally characterized our DAM-like model system, showing that the upregulation of this transcriptional program by HDAC inhibitors leads to an upregulation of amyloid β and pHrodo Dextran uptake – while E.coli uptake is reduced – and a specific reduction of MCP1 secretion in response to IFN-γ and TNF-α. Enhanced amyloid β uptake was confirmed in iPSC-derived microglia. Overall, our strategy for compound-driven microglial polarization offers potential for exploring the function of human DAM and for an immunomodulatory strategy around HDAC inhibition.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 279-293"},"PeriodicalIF":8.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma kynurenine pathway metabolite levels increase in depressed patients after antidepressant treatment","authors":"Romain Colle ,&nbsp;Kenneth Chappell ,&nbsp;Khalil El Asmar ,&nbsp;Bruno Fève ,&nbsp;Philippe Chanson ,&nbsp;Denis J. David ,&nbsp;Céline Verstuyft ,&nbsp;Laurent Becquemont ,&nbsp;Emmanuelle Corruble","doi":"10.1016/j.bbi.2025.05.025","DOIUrl":"10.1016/j.bbi.2025.05.025","url":null,"abstract":"<div><div>The kynurenine (KYN) pathway helps regulate physiological systems implicated in major depressive disorder (MDD). We showed that plasma levels of KYN, kynurenic acid (KA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (3-HAA), and picolinic acid (PA) are lower in depressed individuals. However, whether these levels are restored following treatment with antidepressant drugs (AD) and if this restoration is associated with clinical improvement remains unclear. Fasting plasma levels of tryptophan (TRP) and these metabolites, as well as the KYN/TRP ratio, were investigated in 173 depressed patients of the METADAP cohort and 214 healthy controls of VARIETE. Measures were obtained at baseline and 3 and 6 months after beginning AD treatment. Post-treatment changes in metabolites and their associations with changes in the 17-item Hamilton Depression Rating Scale (HDRS) score were analyzed using linear mixed-effects models. Plasma metabolite levels increased following AD treatment, with significant increases in KA (<em>P_FDR</em> = 0.00014), 3-HAA (<em>P_FDR</em> = 0.034), and PA (<em>P_FDR</em> = 0.0097). The KYN/TRP ratio and KA failed to return to healthy control levels. Increases in the KYN/TRP ratio (coef = -1.08, 95 %CI [-1.92–-0.23], <em>P_FDR</em> = 0.045) and KYN levels (coef = -2.37, 95 %CI [-3.83–-0.91], <em>P_FDR</em> = 0.0011) were significantly associated with HDRS score reductions, indicating depressive symptom improvement. Altogether, we observed increases in plasma KYN pathway metabolite levels in depressed patients following 6 months of AD treatment that, for some, was significantly associated with clinical improvement. Our findings suggest increases in these metabolites may be relevant to treating depression.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 92-99"},"PeriodicalIF":8.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term dynamics of the spinal cord injury neuroinflammatory response and sensory dysfunction in female mice","authors":"Neal J. Wrobel ,&nbsp;Quan Shen ,&nbsp;Dustin H. Kim ,&nbsp;Bahar Adavoody ,&nbsp;Daniela Garcia Prada ,&nbsp;Richard G. Fessler ,&nbsp;Brian T. David","doi":"10.1016/j.bbi.2025.05.024","DOIUrl":"10.1016/j.bbi.2025.05.024","url":null,"abstract":"<div><div>The neuroinflammatory response which takes place within the spinal cord following a traumatic spinal cord injury (SCI) is widely recognized as a major influencer of the progression and severity of the secondary tissue damage which occurs after injury onset. Immunomodulatory therapies aimed at reducing secondary injury are, therefore, a notable point of focus in SCI research. To inform future studies aimed at development of such therapies, we present a detailed characterization of the dynamics of the spinal cord neuroimmune response in mice throughout the first 6 months after contusive SCI.</div><div>Female wild type (C57BL/6) mice received moderate spinal cord contusions at T9 (<em>n</em> = 8/cohort) while control mice remained naïve (<em>n</em> = 6/cohort). Nine terminal assessment time points were included, ranging from 1 day to 6 months post-injury (each timepoint was replicated between one and four times). At each terminal time point, levels of T cells, helper T cells, cytotoxic T cells, regulatory T cells, macrophages, and microglia within the spinal cord were assessed via flow cytometry. Measures of locomotor (open-field task) and sensory (tail flick) function were used to assess behavioral recovery.</div><div>The spinal cord neuroimmune response in mice exhibited a biphasic pattern, with one peak of peripheral immune cell infiltration within the first 2 weeks post-injury, followed by a second peak at 2 months post-injury. Both T cells and macrophages remained elevated in injured spinal cords, relative to controls, at 6 months post-injury. Spinal cord inflammation correlated with exacerbated sensory impairment acutely but correlated with greater normalization of sensory function at 6 months post-injury. Higher inflammation at 6 months post-injury was also associated with an increase in spleen to body mass ratio.</div><div>Together, the results of this investigation highlight the persistent nature of the SCI neuroinflammatory response and indicate that its relationship to other bodily systems continues to evolve even in the late-chronic stage of injury.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 143-156"},"PeriodicalIF":8.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum antineuronal antibodies in patients with post-COVID-19 condition − association to intensive care","authors":"Tatiana Posharina ,&nbsp;Mikko Varonen ,&nbsp;Hanna Jarva ,&nbsp;Mari Kanerva ,&nbsp;Helena Liira ,&nbsp;Sini M Laakso","doi":"10.1016/j.bbi.2025.05.026","DOIUrl":"10.1016/j.bbi.2025.05.026","url":null,"abstract":"<div><div>Post-COVID-19 condition (PCC), characterized by persistent symptoms following SARS-CoV-2 infection, is a global health challenge. Neurological symptoms are common in PCC, and immune-mediated mechanisms have been proposed as potential contributors. We set out to systematically explore serum antineuronal antibodies in patients with PCC and clinical factors associated with seropositivity.</div><div>Our prospective, single-center cohort study included adult patients with a confirmed SARS-CoV-2 infection at least three months prior and a diagnosis of PCC. Serum and cerebrospinal fluid (CSF) samples were analyzed for the presence of antineuronal antibodies. A control group with confirmed SARS-CoV-2 infection but without PCC symptoms was included, age-, sex- and time from acute infection to sampling −matched to seropositive cases of PCC.</div><div>Among 314 consecutive patients with PCC, 38 (12.1 %) tested positive for serum antineuronal antibodies. CSF analysis was performed for a subset; however, no intrathecal autoantibodies were detected. The most prevalent serum autoantibodies targeted CASPR-2 (n = 7, 18.9 %), neurofascin-186 (n = 5, 13.2 %), and glycine receptor (n = 4, 10.8 %). Multinomial logistic regression identified intensive care unit (ICU) admission during acute COVID-19 as the only significant predictor of autoantibody positivity (OR 3.4; 95 % CI: 1.0–10.4). Of the 35 control subjects, two (5.7 %) tested seropositive: one with low titer myelin oligodendrocyte glycoprotein antibodies and another with borderline myelin antibody levels. None of the patients met criteria for autoimmune encephalitis, and neurological assessments and brain magnetic resonance imaging were unremarkable. Neuropsychological testing showed a trend toward impairments in attention and executive functions among seropositive individuals.</div><div>Thus, there was no significant difference in the prevalence of serum antineuronal antibodies in PCC compared to post-infection controls, and the association between seropositivity and ICU admission suggested systemic immune activation rather than a specific autoantibody-mediated mechanism. It remains unclear whether observed neuropsychological deficits are attributable to autoantibodies or the effects of critical illness.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 87-91"},"PeriodicalIF":8.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal markers of immune activation predict cognitive outcomes in Parkinson’s disease","authors":"K.M. Scott ,&nbsp;L.R.B. Spindler ,&nbsp;A.R.D. Peattie ,&nbsp;A. Kouli ,&nbsp;T.D. Fryer ,&nbsp;Y.T. Hong ,&nbsp;M. Camacho ,&nbsp;I. Solim ,&nbsp;L. Kahanawita ,&nbsp;C.H. Williams-Gray","doi":"10.1016/j.bbi.2025.05.020","DOIUrl":"10.1016/j.bbi.2025.05.020","url":null,"abstract":"<div><h3>Background</h3><div>Inflammation is well described in the central nervous system (CNS) and the periphery in Parkinson’s disease (PD) and has been implicated in dementia risk. Longitudinal studies to identify immune/inflammatory biomarkers predicting cognitive decline are lacking.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells and cerebrospinal fluid (CSF)-derived immune cells were obtained from newly-diagnosed PD cases and healthy controls as part of the NET-PDD study. Immunophenotyping was performed using flow cytometry. CSF:blood ratios were calculated as a index of cell ingress to the CNS. Neuroinflammation was evaluated using ¹¹C-PK11195 positron emission tomography (PET) MRI scanning. Participants were then followed-up clinically for 3 years to determine cognitive outcomes.</div></div><div><h3>Results</h3><div>Bivariate comparisons between PD cases who were cognitively impaired at 3 years (PD-CI N = 10), PD non cognitively impaired (PD-NCI, N = 25) and controls (N = 36) identified 22 blood/CSF immune variables that differed between groups. The differences with the largest effect sizes (Cliff’s d) were a higher proportion of activated CD4 T cells in the blood (CD4 + CD28+, d = 0.63) and a higher CSF:blood ratio of memory B cells (d = 0.63) in PD-CI versus controls. The substantia nigra was the only brain region in which PD-CI versus controls showed a higher ¹¹C-PK11195 non-displaceable binding potential (BP_ND) (d = 0.45). In a multivariate regression model including age and gender, the CSF:blood memory B cell ratio and substantia nigra ¹¹C-PK11195 BP_ND at baseline predicted cognitive decline over 3 years. ROC analysis demonstrated that the lead blood, CSF and imaging markers individually predicted cognitive status at 3 years with good accuracy (AUC 0.79–0.85).</div></div><div><h3>Conclusions</h3><div>An increase in activated CD4 cells in the blood, transition of B cells to the CNS and inflammation in the substantia nigra were predictive of longitudinal cognitive outcomes in PD. These markers warrant further validation as biomarkers for immune/inflammatory stratification and add to the evidence supporting development of therapeutic strategies to reduce microglial inflammation or the recruitment of lymphocytes to the CNS in early PD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 165-178"},"PeriodicalIF":8.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomere-mitochondrial dynamics differ depending on childhood maltreatment history, catabolic postpartum state, and developmental period","authors":"R. Nehir Mavioglu ,&nbsp;Anja M. Gumpp ,&nbsp;Elisabeth M. Hummel ,&nbsp;Dirk A. Moser ,&nbsp;Ole Ammerpohl ,&nbsp;Alexander Behnke ,&nbsp;Matthias Mack ,&nbsp;Iris-Tatjana Kolassa","doi":"10.1016/j.bbi.2025.05.022","DOIUrl":"10.1016/j.bbi.2025.05.022","url":null,"abstract":"<div><div>Telomere attrition, a hallmark of aging, is linked to high-energy demand states like early development and biological or psychological stress. Metabolic regulation of telomere length (TL) may occur in these states as part of an energetic trade-off, prioritizing immediate needs over long-term requirements such as telomere maintenance, though this has not been observed in healthy humans. We examined associations between TL and mitochondrial bioenergetics, density, and DNA markers in immune cells of women at 1-week (<em>n</em> = 175) and 1-year postpartum (<em>n</em> = 106), depending on their history of childhood maltreatment (CM), and in their newborns (<em>n</em> = 132). At 1-week postpartum, a catabolic state of high energy demand, women with lower mitochondrial energy production efficiency exhibited shorter TL. One year later, these dynamics appeared only in women with a history of CM. In newborns, TL was shorter when mitochondrial density-normalized routine and ATP production-related respiration was higher. Mitochondrial DNA copy number was associated with TL in both mothers and newborns, regardless of the energetic state. Our findings suggest that telomere-mitochondrial dynamics can adapt to the body’s energetic needs.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 267-278"},"PeriodicalIF":8.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BBI commentary: Breaking barriers: How maternal bacteria influences foetal neurodevelopment","authors":"Philip W.J. Burnet","doi":"10.1016/j.bbi.2025.05.019","DOIUrl":"10.1016/j.bbi.2025.05.019","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 52-53"},"PeriodicalIF":8.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous SARS-CoV-2 Spike protein induces neuroinflammation and alpha-Synuclein accumulation in brain regions relevant to Parkinson’s disease","authors":"Cara Sophie Schreiber ,&nbsp;Lucas Navarro Ramil ,&nbsp;Juliette Bieligk ,&nbsp;Robert Meineke ,&nbsp;Guus Rimmelzwaan ,&nbsp;Christopher Käufer ,&nbsp;Franziska Richter","doi":"10.1016/j.bbi.2025.05.021","DOIUrl":"10.1016/j.bbi.2025.05.021","url":null,"abstract":"<div><div>Background: Coronavirus disease 2019 (COVID-19) frequently presents with neurological symptoms in human patients and leads to long-lasting brain pathology in a hamster model. There is no overt SARS-CoV-2 virus replication in central neurons. Whether viral proteins are sufficient to cause this pathology requires further investigations. The SARS-CoV-2 Spike-protein S1-subunit (S1-protein) has recently gained interest for causing neuroinflammation and accelerating aggregation of alpha-Synuclein (aSyn) in vitro. Here, we show the impact of S1-protein in a broad spectrum of brain regions after injection via three different application routes in C57/BL6 mice. Methods: S1-protein was administered either intranasally, intravenously or intracerebrally. We quantified aSyn immunoreactivity and phosphorylated aSyn (pS129), microglia and astrocyte reactivity, ACE2/Neuropilin-1 receptor expression, and parvalbumin-positive interneurons in limbic system, basal ganglia, and cortical regions 14 days post-application. Plasma cytokine profiles were assessed 6 days post-injection. Results: While intracerebral injection resulted in decreased aSyn immunoreactivity with increased pS129 in males, intravenous injection led to increased levels of aSyn immunoreactivity and microglia cell density, predominantly in brain regions associated with Parkinson’s disease pathology. Intranasal application of S1-protein induced microgliosis in some brain regions but resulted in sex-dependent alterations of aSyn levels, with increases in females and decreases in males. All routes showed sex-dependent alterations in astrocytic reactivity, receptor expression, and parvalbumin-positive interneurons. Conclusion: Our results demonstrate that S1-protein itself leads to neuroinflammation, altered aSyn homeostasis, and disruption of inhibitory circuits in a route- and sex-dependent manner. These findings indicate the possibility of S1-protein being a crucial agent for both neuroinflammatory processes and altered protein regulation mechanisms. S1-protein trapped in tissue reservoirs could therefore explain symptoms occurring or persisting beyond viral clearance (Post COVID-19 condition).</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 102-123"},"PeriodicalIF":8.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The greater splanchnic nerve preferentially regulates neutrophils over macrophages in a rat model of septic peritonitis","authors":"Kathia T. Kato ,&nbsp;Gabriela C.S. Ferreira ,&nbsp;Dennyson L.M. Fonseca ,&nbsp;Eduardo H. Moretti ,&nbsp;Isis F.L. Trzan ,&nbsp;Igor Salerno Filgueiras ,&nbsp;Adriel L. Nobile ,&nbsp;Anny S. Adri ,&nbsp;Monique T. Fonseca ,&nbsp;Rayssa N. Souza ,&nbsp;Caroline M. Matos ,&nbsp;Manoela O.R. Sales ,&nbsp;Caroline A. Lino ,&nbsp;Mariana M. Teramoto ,&nbsp;Sandra M. Muxel ,&nbsp;Otávio Cabral-Marques ,&nbsp;Alexandre A. Steiner","doi":"10.1016/j.bbi.2025.05.015","DOIUrl":"10.1016/j.bbi.2025.05.015","url":null,"abstract":"<div><div>The sympathetic splanchnic nerve is a major player in immunoregulation, but its specific roles during infection have yet to be elucidated. Here, we evaluated how bilateral ablation of the greater splanchnic nerve (SplancX) impacts bacterial burden and immune function in a rat model of <em>E. coli</em>-induced septic peritonitis. SplancX had a major effect on bacterial burden within 24 h, reducing it to 4 % in the peritoneum and to 8 % in the spleen of what was found in the sham-operated controls. Such a major effect was not explained by gross changes in the infiltration of these sites with innate immune cells (neutrophils and macrophages), as assessed by flow cytometry. Single-cell RNA sequencing was then employed to evaluate the cellular activation programs of leukocyte subsets. Of the nine cellular clusters identified in the peritoneum of the infected rats, three of them had a transcriptional signature of activated neutrophils and two of them corresponded to quiescent neutrophils with an immunosuppressive signature. SplancX shifted the balance between these neutrophil subsets in a way consistent with heightened immunity, <em>i.e.</em>, the activated neutrophils were augmented whereas the quiescent neutrophils were reduced in the SplancX group. The remainder of the clusters consisted of macrophages and erythrocytes, none of which changed in a way that could account for the observed effects on bacterial clearance. Confirming that SplancX resulted in heightened neutrophil activation, protein markers of neutrophil degranulation and NETosis were found to be elevated in the peritoneal lavage of the SplancX group. Taken together, the data show that the splanchnic nerve exerts a major effect on bacterial clearance in the acute phase of infection, presumably owing to selective changes in the balance between microbicidal and quiescent subsets of neutrophils.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 30-41"},"PeriodicalIF":8.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SORLA Orchestrates microglial dynamics for enhanced neuroprotection and recovery following ischemic stroke","authors":"Sehui Ma ,&nbsp;Tongmei Zhang ,&nbsp;Junkai Lv ,&nbsp;Shiqi Liang ,&nbsp;Shuaizhu Zhao ,&nbsp;Xinyue Nan ,&nbsp;Ziyue Dou ,&nbsp;Jun Yang ,&nbsp;Youming Lu ,&nbsp;Rong Liu ,&nbsp;Hao Li","doi":"10.1016/j.bbi.2025.05.016","DOIUrl":"10.1016/j.bbi.2025.05.016","url":null,"abstract":"<div><div>This study identifies a novel function of Sortilin-related receptor with A-type repeats (SORLA), traditionally linked to Alzheimer’s Disease (AD) as a high-risk gene and associated with neuronal function, in modulating microglial responses to ischemic stroke. We discovered that SORLA expression is significantly reduced in microglia following stroke, a change linked to increased brain injury and diminished neurological recovery. Utilizing SORLA knockout and overexpression models, we demonstrated its essential role in adjusting microglial inflammatory responses. Notably, microglial-specific overexpression of SORLA not only promoted anti-inflammatory actions and effective phagocytosis but also surpassed traditional concepts of microglial polarization. This overexpression mitigated brain damage and enhanced neurofunctional recovery post-stroke, highlighting the neuroprotective potential of SORLA. This breakthrough challenges the prevailing understanding the role of SORLA and opens new therapeutic possibilities for stroke recovery, indicating its wider relevance for neurodegenerative disease management.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 70-86"},"PeriodicalIF":8.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101442","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}