Brain, Behavior, and Immunity最新文献

{"title":"SARS-CoV2 vaccination during pregnancy – Vetting the impact on maternal health and long-term consequences for offspring brain function","authors":"Anna Gundacker ,&nbsp;Ron Schaer ,&nbsp;Arnold Pollak ,&nbsp;Ulrike Weber-Stadlbauer ,&nbsp;Daniela D. Pollak","doi":"10.1016/j.bbi.2025.04.029","DOIUrl":"10.1016/j.bbi.2025.04.029","url":null,"abstract":"<div><div>The COVID-19 pandemic has shown the critical importance of vaccination strategies to protect vulnerable populations, including pregnant women, from severe disease and its lingering consequences. Although growing evidence demonstrates that COVID-19 vaccines are both safe and highly beneficial during pregnancy, vaccine hesitancy among pregnant women persists, partly fueled by the persistent, decade-old “urban myth” linking vaccination during pregnancy to neuropsychiatric disorders in children.</div><div>Here we used a mouse model of passive immunization with severe acute respiratory syndrome coronavirus 2 spike neutralizing monoclonal antibodies (SaCoV-AB) to determine the effects of gestational COVID-19 vaccination on key pregnancy outcomes, maternal and offspring health, and behavior.</div><div>We show that at a higher SaCoV-AB dosage, maternal immune response is reflected in elevated TNF-α levels in maternal serum, but not in the placenta or the fetal brain, with no effect on pregnancy outcomes. We report no consequences for postpartum maternal care behavior and neonatal communication signatures. Behavioral assessment of adult female and male offspring after maternal SaCoV-AB treatment revealed no differences in phenotypes relevant to neurodevelopmental disorders.</div><div>Our findings indicate that in a preclinical model, passive immunization with SaCoV-AB during pregnancy is well-tolerated, with no discernable impact on maternal or offspring health and behavior.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 549-557"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886585","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 basolateral amygdala and striatum propagate alpha-synuclein pathology causing increased fear response in a Parkinson’s disease model","authors":"Thuy Thi Lai ,&nbsp;Wei Xiang ,&nbsp;Milos Stanojlovic ,&nbsp;Christopher Käufer ,&nbsp;Malte Feja ,&nbsp;Kristina Lau ,&nbsp;Friederike Zunke ,&nbsp;Franziska Richter","doi":"10.1016/j.bbi.2025.04.025","DOIUrl":"10.1016/j.bbi.2025.04.025","url":null,"abstract":"<div><div>Alpha-synuclein (aSyn)-related pathology crucially contributes to the pathogenesis of Parkinson’s disease, a frequent and incurable neurodegenerative disease characterized by progressive motor and non-motor symptoms. Anxiety and fear- related neuropsychiatric symptoms develop frequently and early in the disease, but a lack of understanding of pathogenesis hampers rational therapy. This study aimed to decipher whether aSyn pathology in the basolateral amygdala (BLA) is causative of fear and anxiety. Bilateral stereotaxic injections of human aSyn-preformed amyloid fibrils (PFF) in BLA, striatum, or substantia nigra were conducted in female mice overexpressing human aSyn (Thy1-aSyn) and in wildtype littermates (WT). We characterized the propagation of aSyn pathology and related neuropathological changes across brain regions and examined the behavioral and fear responses in mice up to 2 months post-injection of PFF. While PFF injections induced local aSyn fibril pathology close to all respective injection sites in transgenic mice, we observed differences in propagation, downstream pathology and behavioral alterations. The BLA and the striatum, but not the substantia nigra, effectively propagated aSyn pathology to connected brain regions at 2.5 months post injection. This involved enhanced microgliosis and astrogliosis in the nigrostriatal system and loss of GABAergic parvalbuminergic interneurons in the striatum and corticolimbic brain regions. Intra-BLA PFF injections resulted in increased cued fear response in both transgenic mice and WT mice at 1 month post injection. The effect was more pronounced in the transgenic mice. Conversely, intra-striatal PFF injections enhanced contextual fear in WT at 2 months post injection. These findings imply that increased fear is inducible by aSyn pathology, especially if originating in the BLA or striatum. Furthermore, both regions are hub regions of aSyn pathology propagation, thereby contributing to disease progression. These insights provide mechanisms that can guide rational therapeutic development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 469-486"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878488","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":"Blockage of CCL3 with neutralizing antibody reduces neuroinflammation and reverses Alzheimer disease phenotypes","authors":"Chao Wei ,&nbsp;Jing Liu ,&nbsp;Bing Wu ,&nbsp;Tianhao Shen ,&nbsp;Jiao Fan ,&nbsp;Ye Lin ,&nbsp;Ke Li ,&nbsp;Yane Guo ,&nbsp;Yanchang Shang ,&nbsp;Bo Zhou ,&nbsp;Hengge Xie","doi":"10.1016/j.bbi.2025.04.034","DOIUrl":"10.1016/j.bbi.2025.04.034","url":null,"abstract":"<div><h3>Background</h3><div>Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer’s disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive.</div></div><div><h3>Methods</h3><div>Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice.</div></div><div><h3>Results</h3><div>In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment.</div></div><div><h3>Conclusions</h3><div>Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 400-415"},"PeriodicalIF":8.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864098","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":"Recombinant human DNase treatment mitigates extracellular trap mediated damage and improves long-term recovery after spinal cord injury in male mice","authors":"Shelby K. Reid ,&nbsp;Miranda E. Leal-Garcia ,&nbsp;Ashley V. Tran ,&nbsp;Nicole T. Rehtmeyer ,&nbsp;Isha S. Shirvaikar ,&nbsp;Megan A. Kirchhoff ,&nbsp;Alyson O. Narvaez ,&nbsp;Dylan A. McCreedy","doi":"10.1016/j.bbi.2025.04.033","DOIUrl":"10.1016/j.bbi.2025.04.033","url":null,"abstract":"<div><div>After traumatic spinal cord injury (SCI), inflammation and other reactive processes exacerbate tissue damage and impair long-term motor recovery. Extracellular traps (ETs) are an immune cell effector function first described in neutrophils wherein chromatin is decondensed, decorated with cytotoxic granule enzymes, and expelled from the cell body. Recently, ETs have been linked to poor functional outcomes in SCI; however, translatable agents to prevent ET-mediated damage after SCI have yet to be explored. We assessed recombinant human (rh) DNase (trade name Pulmozyme) as a potential therapeutic that could be repurposed to break down ETs after SCI. To determine the timing of treatment, we characterized the timeline of ET formation in a thoracic contusion model of SCI in mice. We found that ETs levels increased in the injured spinal cord by 4 h post injury (hpi), peaking within 24 hpi. When rhDNase was administered at 1 hpi, DNase activity in the serum remained elevated for 24 hpi with a corresponding increase in circulating ET fragments. At 6 hpi, blood-spinal cord barrier permeability was attenuated in rhDNase-treated animals. Long-term functional hind limb recovery, as assessed by the ladder rung walking test, was improved at 35 dpi in rhDNase-treated animals compared to vehicle-treated controls. RhDNase-treated animals also exhibited shorter SCI lesion lengths at 35 dpi. Altogether, our data demonstrate the potential of rhDNase as an anti-ET therapeutic to improve long-term SCI outcomes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 456-468"},"PeriodicalIF":8.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873872","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":"A pre-existing chronic Toxoplasma gondii infection promotes epileptogenesis and neuropathology in a mouse model of mesial temporal lobe epilepsy","authors":"Tamara L. Baker ,&nbsp;David K. Wright ,&nbsp;Peravina Thergarajan ,&nbsp;Alessandro D. Uboldi ,&nbsp;Anh Vo ,&nbsp;Trevor Wilson ,&nbsp;Christopher J. Tonkin ,&nbsp;Terence J. O’Brien ,&nbsp;Ana Antonic-Baker ,&nbsp;Michael J. Asmussen ,&nbsp;Stuart J. McDonald ,&nbsp;Pablo M. Casillas-Espinosa ,&nbsp;Nigel C. Jones ,&nbsp;Idrish Ali ,&nbsp;Mujun Sun ,&nbsp;Sandy R. Shultz","doi":"10.1016/j.bbi.2025.04.026","DOIUrl":"10.1016/j.bbi.2025.04.026","url":null,"abstract":"<div><h3>Objective</h3><div>There is initial evidence that the common neurotropic parasite <em>Toxoplasma gondii</em> is a risk factor for the development of epilepsy; however, whether it influences epileptogenesis is unknown. This study investigated whether a pre-existing chronic <em>T. gondii</em> infection alters epileptogenesis and neuropathology in a mouse model of mesial temporal lobe epilepsy.</div></div><div><h3>Methods</h3><div>Male and female C57BL/6Jax mice were intraperitoneally administered <em>T. gondii</em> tachyzoites or vehicle control. After 6 weeks, mice underwent self-sustained electrical status epilepticus (SSSE) through an implanted bipolar electrode, or a sham procedure. Continuous video-EEG recordings were taken 0–4- and 12–16-weeks post-SSSE to detect spontaneous seizures. Neuroinflammatory markers were assessed within 1-week post-SSSE, behavior testing was done at 8–12 weeks post-SSSE, and <em>ex vivo</em> MRI was conducted at 16 weeks post-SSSE.</div></div><div><h3>Results</h3><div>Male <em>T. gondii</em> + SSSE mice had an increased incidence of epilepsy compared to Vehicle + SSSE, while female <em>T. gondii</em> + SSSE mice had worse seizure severity compared to non-infected SSSE mice. There was amplified neuroinflammation in both male and female <em>T. gondii</em> + SSSE mice compared to Vehicle + SSSE mice. <em>T. gondii</em> infection in the absence of SSSE also resulted in epilepsy and neuroinflammation. MRI revealed abnormalities in brain morphology in <em>T. gondii</em> + SSSE male and female mice and changes in white matter integrity in male <em>T. gondii</em> + SSSE mice, compared to both non-infected SSSE and <em>T. gondii</em> control mice. SSSE and <em>T. gondii</em> infection impacted anxiety and spatial memory in males, and anxiety and social behavior in females.</div></div><div><h3>Interpretation</h3><div>These findings demonstrate that a chronic <em>T. gondii</em> infection can result in epilepsy, and that a pre-existing <em>T. gondii</em> infection exacerbates epileptogenesis following a brain insult, in mice.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 440-455"},"PeriodicalIF":8.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874413","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":"Investigating the relationship between toll-like receptor activity, low-grade inflammation and cognitive deficits in schizophrenia patients – A mediation analysis","authors":"Saahithh Redddi Patlola ,&nbsp;Laurena Holleran ,&nbsp;Maria R. Dauvermann ,&nbsp;Karolina Rokita ,&nbsp;Aodán Laighneach ,&nbsp;Brian Hallahan ,&nbsp;Ross McManus ,&nbsp;Marcus Kenyon ,&nbsp;Colm McDonald ,&nbsp;Derek W. Morris ,&nbsp;John P. Kelly ,&nbsp;Gary Donohoe ,&nbsp;Declan P. McKernan","doi":"10.1016/j.bbi.2025.04.024","DOIUrl":"10.1016/j.bbi.2025.04.024","url":null,"abstract":"<div><h3>Background</h3><div>Schizophrenia is a debilitating psychiatric illness. Many studies report alterations in immune biomarkers (cytokines) in such patients. In addition, such prolonged low-grade inflammatory responses are associated with lowered cognitive performance. In this study, we investigated whether the expression and activity of Toll-like receptors (TLRs), receptors involved in initiating innate immune responses, are associated with the reported immune changes and, if so, whether they are associated with cognitive deficits in such patients.</div></div><div><h3>Methods</h3><div>300 participants (202 healthy controls (HC) and 98 patients with schizophrenia (SZ)) were recruited. A battery of cognitive tasks using WAIS-III and CANTAB were administered to the participants. Whole blood collected from participants was used to assess TLR2, 3, and 4 activity. mRNA expression of cytokines and TLR1-10 were quantified using RT-QPCR. Using ELISA, plasma was analysed for basal levels of cytokines such as IL-6, IL-8, IL-10, IL-12, TNF-α, IFN-γ and C-reactive proteins (CRP).</div></div><div><h3>Results</h3><div>We found significantly elevated plasma levels of IL-6, IL-8, IL-10, TNF-α, and CRP in the SZ group. In the SZ patient-only group, significantly higher levels of TLR2 and −4 activity (as measured by IL-6, IL-8, and IL-10 release following agonist stimulation) were observed. Significant negative associations in patients were observed between plasma IL-6 levels and measures of attention &amp; processing speed and working memory; IL-8 and intelligence quotient; TNF-α and logical memory; and social cognition and IL-10 and CRP. Multiple-linear regression analysis suggests that TLR2 and TLR4 activity was associated with increased and decreased cytokine levels respectively and decreased cognitive performance. Finally, the significant association between TLR activity and decreased cognitive performance was mediated by IL-6 and IL-8.</div></div><div><h3>Conclusion</h3><div>We have demonstrated that patients with schizophrenia have elevated protein and mRNA expression of a range of cytokines and Toll-like receptors. Some of these changes are associated with deficits in cognition. Finally, our study has demonstrated a modest relationship between TLR activity and cognitive deficits in schizophrenia patients in a manner that may be mediated by IL-6 and IL-8.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 529-539"},"PeriodicalIF":8.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886468","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 “Microbiome-derived indole-3-lactic acid reduces amyloidopathy through aryl-hydrocarbon receptor activation” [Brain Behav. Immun. 122 (2024) 568–582]","authors":"Hyun Kim ,&nbsp;Eunkyung Lee ,&nbsp;Mincheol Park ,&nbsp;Kyungchan Min ,&nbsp;Yen N. Diep ,&nbsp;Jinhong Kim ,&nbsp;Hyeok Ahn ,&nbsp;Eulgi Lee ,&nbsp;Sujeong Kim ,&nbsp;Yunjae Kim ,&nbsp;You Jung Kang ,&nbsp;Joon Hyung Jung ,&nbsp;Min Soo Byun ,&nbsp;Yanghyun Joo ,&nbsp;Chanyeong Jeong ,&nbsp;Dong Young Lee ,&nbsp;Hansang Cho ,&nbsp;Hansoo Park ,&nbsp;Tae Kim","doi":"10.1016/j.bbi.2025.03.033","DOIUrl":"10.1016/j.bbi.2025.03.033","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Page 423"},"PeriodicalIF":8.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961382","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 specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice","authors":"Rui-Kang Pang ,&nbsp;Jia-Yi Zheng ,&nbsp;Hao-You Xu ,&nbsp;Yuan-Qi Zhao ,&nbsp;Shan Su ,&nbsp;Kai Le ,&nbsp;Ye-Feng Cai ,&nbsp;Shi-Jie Zhang ,&nbsp;Xiao-Xiao Li","doi":"10.1016/j.bbi.2025.04.015","DOIUrl":"10.1016/j.bbi.2025.04.015","url":null,"abstract":"<div><div>Depression is an early clinical manifestation of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), although the underlying molecular mechanisms remain poorly elucidated. The objective of this study was to investigate the mechanisms underpinning depressive behavior in the context of ALSP, utilizing microglial-specific <em>Csf1r</em> haploinsufficient mice. Our findings indicate that these mice exhibited depressive-like behaviors, as well as microglial hyper-ramification and aberrant synaptic pruning capacity. Blockade of CSF1R signaling with PLX3397 resulted in significant amelioration of depressive symptoms and restoration of normal microglial morphology and function. RNA sequencing analysis of microglia isolated from the medial prefrontal cortex (mPFC) of the brain indicated that NLRPs signaling pathways may play a significant role in the observed alterations in microglial <em>Csf1r</em> haploinsufficient mice. Notably, NLRP6, rather than NLRP3, was found to be upregulated, and the expression of caspase-1 exhibited colocalization with the microglial marker Iba1. Pharmacological inhibition of caspase-1 using VX-765 improved depressive-like behaviors, as well as microglial function. Taken together, our findings delineate a causal relationship between microglial <em>Csf1r</em> haploinsufficiency-induced activation of the NLRP6/caspase-1 signaling pathway and the manifestation of depressive-like behaviors in ALSP mice.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 383-399"},"PeriodicalIF":8.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859174","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":"CMPK2 facilitates pain sensitization by promoting the lactylation and deactivation of cGAS-STING pathway in neuropathic pain","authors":"Mei Yang ,&nbsp;Erliang Kong ,&nbsp;Honghao Song ,&nbsp;Xiaochen Zhang ,&nbsp;Xudong Feng ,&nbsp;Tong Hua ,&nbsp;Huawei Wei ,&nbsp;Qianbo Chen ,&nbsp;Hongbin Yuan","doi":"10.1016/j.bbi.2025.04.016","DOIUrl":"10.1016/j.bbi.2025.04.016","url":null,"abstract":"<div><div>Neuropathic pain, a complex condition arising from nerve damage, presents significant challenges in pain management, driving extensive research into its molecular mechanisms. Our mRNA microarray analysis identified cytosine monophosphate kinase 2 (CMPK2) as a key player in the progression of neuropathic pain, but the molecular mechanism remains to be elusive. By western blotting and <em>Q</em>-PCR, we observed a notable upregulation of CMPK2, particularly in microglia of the spinal dorsal horn during neuropathic pain. <em>In vivo</em> and <em>in vitro</em> experiments demonstrated that <em>Cmpk2</em> deficiency significantly alleviated neuropathic pain and neural injury by increasing the production of type I interferons (IFN-I), which are known for their analgesic properties. Conversely, overexpression of <em>Cmpk2</em> in microglia led to a marked decrease in IFN-I production <em>in vitro</em>. Further investigation revealed that the transcription factor RUNX1 promoted CMPK2 upregulation in microglia. Mechanistically, we found that CMPK2 exacerbated neuropathic pain by enhancing glycolysis in microglia, resulting in increased lactate production. This accumulation of lactate induced lactylation and deactivation of the stimulator of interferon genes (STING), which was responsible for IFN-I production. These findings suggested that CMPK2 facilitated pain sensitization by promoting microglial glycolysis, resulting in the increased lactylation and deactivation of the cGAS-STING pathway in neuropathic pain, highlighting the potential of targeting CMPK2 for therapeutic intervention in neuropathic pain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 370-382"},"PeriodicalIF":8.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855710","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":"Sustained NPSLE-like phenotype in the absence of systemic lupus-like disease in TLR7-deficient B6.Nba2 mice","authors":"Audrey Kwun ,&nbsp;James K. Sullivan ,&nbsp;John Shelestak ,&nbsp;Kayla M. Merritt ,&nbsp;Selena S. Liu ,&nbsp;Gabrielle Mey ,&nbsp;Tara DeSilva ,&nbsp;Trine N. Jørgensen","doi":"10.1016/j.bbi.2025.04.017","DOIUrl":"10.1016/j.bbi.2025.04.017","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the role of Toll-like Receptor 7 (TLR7) in the development of neuropsychiatric lupus (NPSLE) in the B6.Nba2 murine model of SLE.</div></div><div><h3>Methods</h3><div>TLR7-deficient B6.Nba2 mice were evaluated for the development of NPSLE symptoms through behavioral testing with comparison groups of wild-type NPSLE-prone B6.Nba2 and B6 controls. Behavioral testing results were evaluated in the context of biomarker data, including flow cytometry for immune cell activation, and enzyme-linked immunosorbent assays (ELISA) to measure serum cytokine and autoantibody levels, including autoantibodies against double stranded DNA (dsDNA) and DWEYS peptide. Brain and spleen tissues waere harvested, and immuno histochemical studies and inflammatory gene activation obtained via qPCR were further analyzed to characterize immune system activation and SLE and NPSLE development in the mice.</div></div><div><h3>Results</h3><div>TLR7-deficient mice exhibited reduced signs of systemic SLE, including decreased splenomegaly, anti-dsDNA titers, and immune cell activation compared to wild-type mice. However, TLR7-deficient mice displayed a similar behavioral pattern to the NPSLE-prone B6.Nba2 mice, indicating NPSLE development was not influenced by TLR7. Knockout of TLR7 in B6.Nba2 mice also led to increased expression of TLR4 and TLR9, which suggests a possible role for these receptors in NPSLE pathogenesis.</div></div><div><h3>Conclusion</h3><div>While systemic lupus-like disease in the B6.Nba2 mouse model is dependent on TLR7, NPSLE development is not and may be influenced by TLR4 and TLR9 signaling. Thus, there may be separate mechanisms driving peripheral SLE compared to NPSLE with possible implications for pharmacologic management.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 352-361"},"PeriodicalIF":8.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850475","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}