Brain, Behavior, and Immunity最新文献

{"title":"Crosstalk between DNA damage and cGAS-STING immune pathway drives neuroinflammation and dopaminergic neurodegeneration in Parkinson’s disease","authors":"Sazzad Khan ,&nbsp;David F. Delotterie ,&nbsp;Jianfeng Xiao ,&nbsp;Ramasamy Thangavel ,&nbsp;Roderick Hori ,&nbsp;James Koprich ,&nbsp;Stephen E. Alway ,&nbsp;Michael P. McDonald ,&nbsp;Mohammad Moshahid Khan","doi":"10.1016/j.bbi.2025.106065","DOIUrl":"10.1016/j.bbi.2025.106065","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by substantial degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum, leading to debilitating motor and non-motor impairments. Recent studies provide clues on the pathogenic role of DNA damage in age-related neurodegenerative diseases, but the molecular mechanisms of DNA damage response in PD remain poorly understood. We found that the accumulation of DNA double-strand breaks (DDSBs), and/or DNA repair deficits, are key in the pathogenesis of PD and drives cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) immune regulatory pathway, contributing to neuroinflammation and dopaminergic neurodegeneration in human postmortem PD and non-PD brains as well as in experimental models of PD. We observed enhanced expression of γ-H2A.X (Ser139) a biomarker of DDSB, and decreased levels of DNA repair proteins in the brains of human PD compared to non-PD brains. This was positively correlated with upregulation of STING immune response pathways, microglial activation, senescence and dopaminergic neurodegeneration. Similarly, we observed increased and sustained DDSB as assessed by γ-H2A.X (Ser139) immunoreactivity, and degeneration of tyrosine hydroxylase-positive neurons in primary neuron/glia cultures and mice treated with 1-methyl-4-phenylpyridine (MPP+) or 1,2,3,6-tetrahydropyridine (MPTP). Next, we employed a mouse model of α-synucleinopathy, which exhibited elevated DDSBs alongside overactivation of the DNA-sensing cGAS-STING pathway and type-I interferon signaling, in association with dopaminergic neurodegeneration. Interestingly, pharmacological and genetic ablation of STING reduces DDSB, limits inflammatory response, improves behavioral function and attenuates the loss of dopaminergic neurons in this model. Our findings suggest that the accumulation of DDSBs and/or dysregulation in DNA repair proteins activate cGAS-STING mediated immune responses in the brain, potentially exacerbating dopaminergic neurodegeneration in PD. Furthermore, regulating these processes is essential for alleviating the pathological effects of PD and may offer potential therapeutic strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106065"},"PeriodicalIF":7.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757545","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":"Traumatic brain injury induces a sustained sensorimotor impairment associated with a dysregulated acute phase response in mice overexpressing human amyloid precursor protein","authors":"Ross E. McLeod ,&nbsp;Kush M. Kale ,&nbsp;Caroline Weglinski ,&nbsp;Anwar Masoud ,&nbsp;Naveed Akbar ,&nbsp;Fay Probert ,&nbsp;Daniel C. Anthony ,&nbsp;Jaezah Zainal","doi":"10.1016/j.bbi.2025.07.027","DOIUrl":"10.1016/j.bbi.2025.07.027","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) significantly contributes to morbidity and mortality worldwide, often leading to cognitive decline. Although there is a recognised link between TBI and the acceleration of Alzheimer’s disease (AD), the precise biological mechanisms driving this relationship are not fully understood. While several studies have investigated TBI in AD mouse models, none have examined the role of systemic inflammation in this context. In this study, we investigated the inflammatory responses, both centrally and peripherally, in 1-year-old wild-type (WT) and J20 mice (Tg:PDGFB-APPSwInd), overexpressing human amyloid precursor protein with the Swedish and Indiana mutations. Following controlled cortical impact (CCI) at 0.5 mm depth to the left somatosensory cortex, we examined outcomes at 1 and 7 days post-injury. The J20 mice exhibited a persistent sensorimotor impairment post-TBI, as determined by the adhesive removal test. Although amyloid-β42 deposition progressively increased post-injury, this behavioural deficit was not associated with greater neuronal loss compared to WT mice. Using qPCR, it was revealed that the level of proinflammatory cytokine and chemokine expression in the brain was largely conserved between WT and J20 mice, though brain <em>Cxcl10</em> expression increased by 28.6 % in J20 mice at 7d-post injury compared to WT. However, J20 mice exhibited an exaggerated acute phase response (APR) to the TBI in the liver and spleen at 7d. Accompanying the potentiated APR, ¹H NMR revealed that plasma glucose was decreased in J20 mice compared to WT at 7d. Taken together, this suggests that the sustained sensorimotor deficit in J20 mice is associated with increased amyloid-β pathology, and a dysregulated and prolonged systemic inflammatory response, accompanied by hypoglycaemia. In general, TBI in the presence of AD pathology, results in extended systemic inflammatory and metabolic responses that are likely to underpin the extended cognitive impairment, and our findings emphasise the need for customised interventions that address central and systemic inflammation after TBI in individuals with neurodegenerative disease.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 975-988"},"PeriodicalIF":7.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757550","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":"Microglia depletion in a mouse model of prenatal and postnatal immune activation","authors":"Naomi Ciano Albanese ,&nbsp;Ignacio Del Castillo ,&nbsp;Giulia Ragaglia ,&nbsp;Giulia Castellano ,&nbsp;Maria Antonietta Ajmone-Cat ,&nbsp;Roberta De Simone ,&nbsp;Marilena Griguoli ,&nbsp;Laura Ricceri","doi":"10.1016/j.bbi.2025.07.018","DOIUrl":"10.1016/j.bbi.2025.07.018","url":null,"abstract":"<div><div>Risk for neurodevelopmental disorders can be related to early immune stimulations and altered brain microglial functions. Here we investigated the behavioural and electrophysiological effects of microglia depletion in a mouse model of developmental immune activation.</div><div>C57BL/6J pregnant mice were exposed on gestational day 12.5 to polyinosinic:polycytidylic acid (Poly I:C), subsequently, on postnatal day 9, offspring was further treated with lipopolysaccharide (LPS). At weaning, offspring was exposed throughout adolescence (4 weeks) to either a diet containing Colony Stimulating Factor-1 receptor inhibitor (PLX5622, PLX) to reduce microglia, or standard diet. Hence, we assessed i) explorative and anxiety-like responses, social responsiveness and cognitive abilities between 7^th and 8^th postnatal week; ii) synaptic transmission and neuroinflammatory and microglial molecular markers in the medial prefrontal cortex (mPFC) and hippocampus (HP) at the end of treatment (8^th postnatal week).</div><div>EIA condition reduced locomotor activity and impaired discrimination between a familiar and a novel social stimulus (social novelty response) only in male mice. Also, PLX treatment selectively affected the same social novelty response in males (both saline and EIA) and in EIA females, intriguingly sparing saline females. Unexpectedly, EIA condition <em>per se</em> did not affect spontaneous excitatory and inhibitory synaptic transmission in both mPFC and HP, whereas EIA combined with PLX reduced inhibitory transmission in males (both mPFC and HP) and neuron excitability in both male and female mPFC. Interestingly, PLX had <em>per se</em> sex- and region- specific effects increasing inhibitory transmission in female mPFC and decreasing excitatory transmission in male HP.</div><div>Molecular data, beside a robust downregulation of microglia markers in PLX diet groups, also showed that EIA condition increased interleukin-6 (<em>il-6</em>) expression in EIA males in both mPFC and HP, and elevated <em>il-1β</em> levels in both sexes in mPFC and in male HP.</div><div>Overall, these findings indicate that males have an increased vulnerability to the long-term behavioural and inflammatory effects of the EIA condition, and are more likely to exhibit behavioural and electrophysiological changes in response to microglia depletion.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 935-947"},"PeriodicalIF":7.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738914","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":"Corrigendum to “Pretreatment with dimethyl fumarate prevents chronic pain and its comorbidities via Nrf2 pathway in a rat model of neuropathic pain” [Brain Behav. Immunity 128 (2025) 725–736]","authors":"Anh Cong Tuan Le ,&nbsp;Juliana Fiuza-Fernandes ,&nbsp;Joana Margarida Silva ,&nbsp;Mariana Teixeira Sampaio ,&nbsp;Andreia Teixeira-Castro ,&nbsp;Sara Duarte-Silva ,&nbsp;Hugo Leite-Almeida","doi":"10.1016/j.bbi.2025.07.008","DOIUrl":"10.1016/j.bbi.2025.07.008","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Page 1039"},"PeriodicalIF":7.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741237","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":"Genotype and microbiome shape immunity in a sex-specific manner in mouse models of Alzheimer’s disease","authors":"John W. Bostick ,&nbsp;T. Jaymie Connerly ,&nbsp;Taren Thron ,&nbsp;Brittany D. Needham ,&nbsp;Matheus de Castro Fonseca ,&nbsp;Rima Kaddurah-Daouk ,&nbsp;Rob Knight ,&nbsp;Sarkis K. Mazmanian","doi":"10.1016/j.bbi.2025.07.028","DOIUrl":"10.1016/j.bbi.2025.07.028","url":null,"abstract":"<div><div>Preclinical studies have revealed that the microbiome broadly affects immune responses and deposition and/or clearance of amyloid-beta (Aβ) in mouse models of Alzheimer’s disease (AD), but whether, and how, the microbiome shapes central and peripheral immune profiles in AD models remains unknown. We examined adaptive immune responses in two mouse models containing AD-related genetic predispositions (3xTg and 5xFAD) in the presence or absence of the microbiome to determine if it promotes dysregulated immune responses and cognition in AD. T and B cells were altered in central nervous system (CNS)-associated lymph nodes and systemic immune tissues between genetic models and wildtype mice, with earlier signs of heightened immune activity in females. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in increased cognitive deficits, primarily in males. These data reveal sexual dimorphism in early signs of immune activity and microbiome effects, and highlight how sex and the microbiome shape responses in mouse models of AD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 1014-1027"},"PeriodicalIF":7.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752369","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":"Can catastrophes be opportunities? A randomized clinical trial testing a brief mindset intervention for reducing inflammation and depression following COVID-19","authors":"Jesse A. Barrera ,&nbsp;Lexi D. Straube ,&nbsp;Zoë Huml ,&nbsp;Rachael M. Yielder ,&nbsp;Sean R. Zion ,&nbsp;Kristopher M. Evans ,&nbsp;Kengthsagn Louis ,&nbsp;Daniel P. Moriarity ,&nbsp;Chiara Gasteiger ,&nbsp;George M. Slavich ,&nbsp;Alia J. Crum","doi":"10.1016/j.bbi.2025.07.011","DOIUrl":"10.1016/j.bbi.2025.07.011","url":null,"abstract":"<div><div>Survivors of major catastrophes face significant mental health risks but may also experience growth in meaning, relationships, and self-esteem. Two years after the onset of the Coronavirus disease 2019 (COVID-19) pandemic, we conducted a randomized clinical trial to test the effects of an intervention that promotes the mindset that “catastrophes can be opportunities in the long-term” on mental health and well-being. Adults were randomized to a mindset intervention (<em>n</em> = 226) or control group (<em>n</em> = 153). The mindset group watched five brief videos that reinforced that “catastrophes can be opportunities in the long-term” and wrote about their mindsets toward the COVID-19 pandemic and how these might encourage or discourage post-traumatic growth. The control group watched videos on the chronology of the pandemic and completed questions reviewing their knowledge. Mindsets regarding catastrophes-as-opportunities, post-traumatic growth, anxiety, depression, and the inflammatory marker C-reactive protein (CRP) were assessed. The mindset intervention significantly reduced CRP (<em>p</em> = 0.030) and depressive symptom levels (<em>p</em> = 0.009) at 3 months post-intervention. In addition, changes in mindset significantly mediated the effects of the intervention on posttraumatic growth, depressive symptoms, and other domains of mental health and well-being. Brief mindset interventions may thus have beneficial biological and clinical effects for individuals going through major catastrophes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 1028-1038"},"PeriodicalIF":7.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752368","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":"Maternal imprinting of autoreactivity in a murine model of systemic lupus erythematosus","authors":"Sofie V. Fonager ,&nbsp;Gudrun Winther ,&nbsp;Yamira C.L. Weber ,&nbsp;Thomas R. Wittenborn ,&nbsp;Kristian S. Kastberg ,&nbsp;Ewa Terczyńska-Dyla ,&nbsp;Lisbeth Jensen ,&nbsp;Lisbeth A. Hansen ,&nbsp;Michael C. Carroll ,&nbsp;Yonglun Luo ,&nbsp;Lin Lin ,&nbsp;Søren E. Degn","doi":"10.1016/j.bbi.2025.07.025","DOIUrl":"10.1016/j.bbi.2025.07.025","url":null,"abstract":"<div><div>Mammals confer passive immunity upon their offspring via transplacental IgG and postnatal transfer of milk IgA. Maternofetal microchimerism and the cytokine environment <em>in utero</em> may also influence the developing offspring. Normally protective maternal immune factors can adversely affect the offspring in the context of maternal autoimmune disease. Here, unexpectedly, we observed maternal imprinting of autoreactivity, presenting as spontaneous germinal centers (GCs) and endogenous autoantibody production, in a murine model of systemic lupus erythematosus (SLE). This prompted us to investigate how maternal autoimmune status can influence the offspring independently of genetic factors. Using embryo transfers to experimentally uncouple genetic from environmental maternal factors, we did not observe maternofetal microchimerism, but embryo transfer offspring of autoimmune dams received maternally derived IgG2A and anti-dsDNA antibodies. Moreover, they displayed increased formation of spontaneous GCs and elevated endogenous IgG2C autoantibody production. The neuroimmunological phenotype in offspring appeared unaffected. Taken together, our findings suggest maternal immune factors actively contribute to shape the susceptibility of offspring to autoimmune diseases independent of genetic factors.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 921-934"},"PeriodicalIF":7.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739008","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":"IRF7 in peripheral monocytes drives BBB disruption in anti-NMDAR encephalitis","authors":"Qihui Li ,&nbsp;Li Xiao ,&nbsp;Jianfang Li ,&nbsp;Yu Huang ,&nbsp;Shishi Shen ,&nbsp;Huilu Li ,&nbsp;Fuhua Peng ,&nbsp;Huichang He ,&nbsp;Shen Huang ,&nbsp;Jian Sun ,&nbsp;Wei Qiu ,&nbsp;Wei Cai ,&nbsp;Yaqing Shu","doi":"10.1016/j.bbi.2025.07.026","DOIUrl":"10.1016/j.bbi.2025.07.026","url":null,"abstract":"<div><div>Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe neurological disorder characterized by the presence of autoantibodies against the NMDAR and blood–brain barrier (BBB) disruption. This study investigates the involvement of monocytes and interferon regulatory factor 7 (IRF7) in BBB leakage of this disease. In anti-NMDAR encephalitis patients, the circulating monocytes count was positively correlated with BBB disruption, besides, IRF7 was activated in these cells. In peripheral blood and brain of our anti-NMDAR encephalitis mouse model, increased monocytes and elevated IRF7 expression within these cells were found. Additionally, in the blood and brain of this model, the quantity of monocytes and their IRF7 expression level were positively correlated with behavioral deficits. IRF7-KO mice were subjected to anti-NMDAR encephalitis modeling and exhibited milder disease severity and reduced BBB disruption compared to their WT counterparts. Bone marrow derived macrophages (BMDMs) from IRF7-KO mice showed diminished capacity to disrupt BBB compared with BMDMs from WT mice in <em>in vitro</em> study. Our findings suggest that IRF7 plays a critical role in the pathogenesis of anti-NMDAR encephalitis by modulating monocyte’s capacity to disrupt BBB. Targeting IRF7 may offer a novel therapeutic strategy for this devastating neurological condition.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 960-974"},"PeriodicalIF":7.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749446","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 sympathetic nervous system enhances host immune responses to enteric bacterial pathogens in mice","authors":"Emmy Tay,&nbsp;Michael Cremin,&nbsp;Kristina Sanchez,&nbsp;Elliot Llyod,&nbsp;Ingrid Brust-Mascher,&nbsp;Colin Reardon","doi":"10.1016/j.bbi.2025.07.014","DOIUrl":"10.1016/j.bbi.2025.07.014","url":null,"abstract":"<div><div>Mucosal immune responses to enteric bacterial infections are highly coordinated processes that orchestrate host protection while minimizing the potential for immune-triggered pathology. In the intestinal tract, bidirectional communication occurs between the nervous and immune systems to affect local immune responses by modulating the activity of resident and recruited immune cells, and indirectly on the supporting stromal cells. These neuroimmune signaling pathways that alter host defense have focused on specialized sensory innervation and the unique neurotransmitters released from them. Although the sympathetic nervous system has been established to induce a tissue-protective phenotype in subpopulations of neuron-associated macrophages in the small intestine, the role of these neurons during enteric bacterial infection was unknown. Using genetic labeling of activated neurons with <em>Arc</em>TRAP, we demonstrate that colonic infection in mice induces activation of the rostral ventrolateral medulla, a major sympathetic center in the brainstem. The importance of peripheral sympathetic neurons was further demonstrated using chemical sympathectomy that significantly increased bacterial burden during <em>Citrobacter rodentium</em> (<em>C. rodentium</em>) infection in mice. Increased bacterial burden was matched by a deficit in host protection due to reduced IFNγ production by colonic CD4 + T-cells. Sympathectomy, however, did not diminish the capacity to differentiate into IFNγ- or IL-17A-producing T-cells <em>in vitro</em>, suggesting that the lack of sympathetic innervation during infection may alter this process <em>in vivo</em> without causing sustained T-cell intrinsic defects. In assessing which receptors could mediate these effects, pharmacological antagonists selective for α-adrenergic receptors (αAR), but not β-adrenergic receptors, increased bacterial burden and reduced colonic IFNγ production. Using isolated cell types from the colon of uninfected and infected mice, we identified the αΑR subtypes expressed on immune and stromal cells, with significant upregulation of these receptors on T-cells during <em>C. rodentium</em> infection. Together these data demonstrate the unique role of the sympathetic nervous system and αAR in mucosal immune responses against enteric bacterial pathogens.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 898-909"},"PeriodicalIF":7.6,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739007","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 moderating role of lifetime social engagement on the relationship between C-reactive protein and negative symptoms among young adults at clinical high risk for psychosis","authors":"David R. Goldsmith ,&nbsp;Qingyue E. Yuan ,&nbsp;Jean Addington ,&nbsp;Carrie E. Bearden ,&nbsp;Kristin S. Cadenhead ,&nbsp;Tyrone D. Cannon ,&nbsp;Ricardo E. Carrión ,&nbsp;Matcheri Keshavan ,&nbsp;Daniel H. Mathalon ,&nbsp;Diana O. Perkins ,&nbsp;William S. Stone ,&nbsp;Ming T. Tsuang ,&nbsp;Scott W. Woods ,&nbsp;Elaine F. Walker ,&nbsp;Benson S. Ku","doi":"10.1016/j.bbi.2025.07.023","DOIUrl":"10.1016/j.bbi.2025.07.023","url":null,"abstract":"&lt;div&gt;&lt;div&gt;One potential mechanism that may contribute to the development of negative symptoms is inflammation. Inflammatory markers have been shown to be elevated in Clinical High Risk for Psychosis (CHR-P) individuals and may be associated with negative symptoms. Social engagement in early developmental periods may decrease stress and interact with downstream processes, such as inflammation. Herein, we hypothesized that lifetime social engagement may moderate the association between C-Reactive Protein (CRP), a marker of inflammation, and negative symptoms in CHR-P young adults and healthy controls (HC) such that this association would be significant only among those at CHR-P with lower, but not greater, social engagement. 48 individuals (30 CHR-P and 18 healthy controls; HC) from the North American Prodromal Longitudinal Study (NAPLS)-2 cohort, were included in this analysis. Negative symptoms were assessed using the Scale of Psychosis-risk Symptoms (SOPS), and social engagement was calculated using the Life Events Stress scale. A generalized linear model with robust estimation was used to test the association of CRP, diagnosis, and social engagement (and their interactions) with negative symptoms, adjusting for age, sex, ethnicity, childhood poverty, and depressive symptoms. Simple slopes for the association between negative symptoms and CRP moderated by social engagement were calculated and stratified by CHR-P groups. CHR-P subjects had significantly greater negative symptoms than HC subjects (p &lt; 0.001), though there was no significant difference in CRP values or social engagement. In the generalized linear models of the whole sample, negative symptoms were significantly associated with CRP (β = 1.34, SE = 1.35, 95 %CI −1.31–4.00, p = 0.035) as well as CHR-P (β = 8.16, SE = 1.71, 95 %CI 4.80–11.52, p &lt; 0.001). There was a significant association between negative symptoms and the interaction of CRP-by-social engagement (β = 0.37, SE = 0.56, 95 %CI −0.74–1.47, p = 0.008), but not the interaction of CRP-by-CHR-P or CHR-P-by-social engagement (both p &gt; 0.25). There was a significant association between negative symptoms and the three-way interaction of CRP-by-CHR-P-by-social engagement (β = −5.27, SE = 1.70, 95 %CI −8.60 to −1.94, p = 0.002). Based on the simple slopes analysis, we observed a significant positive association between negative symptoms and CRP amongst the CHR-P group at low (−1SD; p = 0.02) and mean levels of social engagement (p = 0.04) but not in the individuals with high social engagement (+1SD; p = 0.34) or in any of the HC social engagement levels (p all &gt; 0.2). In this sample of CHR-P individuals, there was an association between negative symptoms and the interaction between diagnosis, CRP, and social engagement, adjusting for relevant clinical and demographic covariates. Greater engagement in social activities appeared to buffer the relationship between inflammation, as measured by CRP, and negative symptoms. The","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 890-897"},"PeriodicalIF":7.6,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724595","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}