Journal of Neuroinflammation最新文献

{"title":"Single-cell transcriptomic landscape of sciatic nerve after transection injury.","authors":"Yiben Ouyang, Mingqian Yu, Tieyuan Zhang, Haofeng Cheng, Liang Zuo, Haolin Liu, Yanjun Guan, Ao Liu, Jiajie Chen, Ruichao He, Sice Wang, Tianqi Su, Yixiao Tan, Yuhui Cu, Xiaochun Zhang, Xiaoyang Fu, Junli Wang, Jinjuan Zhao, Jiang Peng, Yu Wang","doi":"10.1186/s12974-025-03514-3","DOIUrl":"https://doi.org/10.1186/s12974-025-03514-3","url":null,"abstract":"<p><p>Peripheral nerve injuries, particularly those affecting the sciatic nerve, often result in incomplete functional recovery due to the limited regenerative capacity of adult peripheral nerves. To elucidate the cellular and molecular mechanisms underlying nerve regeneration, we performed single-cell RNA sequencing (scRNA-seq) on rat sciatic nerve tissues at seven time points (Days 0, 1, 3, 5, 7, 10, and 14) following transection injury. Through unsupervised clustering, we identified four major cellular compartments-neurofibroblasts (NFs), glial cells (Glis), immune cells, and vascular cells-and delineated their dynamic trajectories during regeneration. Early responses were dominated by macrophage (Mac) and granulocyte infiltration (Day 1), followed by proliferative expansion of proliferating mesenchymal fibroblasts (NF5) and repair Schwann cells (Gli0) by Days 3-5. Vascular remodeling commenced from Day 7, while Glis progressively transitioned to mature myelinating states (Gli2/Gli5) by Day 14. Pseudotime analysis revealed subtype-specific reprogramming in both Macs and Glis, and cell-cell communication analysis uncovered key ligand-receptor interactions-particularly collagen and PTN signaling between Macs, NFs, and Glis. Bulk transcriptomic validation confirmed sustained and spatially distinct activation of the TGF-[Formula: see text] signaling pathway across cell types and anatomical locations. Comparative analysis with a sciatic nerve crush injury model revealed a stronger early immune response and delayed Gli recovery in transection injury, indicating a narrowed therapeutic window. Together, this work provides a time-resolved single-cell atlas of peripheral nerve regeneration, defines key regulatory circuits within the immune-NF-Gli axis, and identifies phase-specific therapeutic targets-such as early Mac heterogeneity, NF4-mediated matrix remodeling, and Schwann cell remyelination-for enhancing functional recovery following severe nerve injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"205"},"PeriodicalIF":10.1,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphisms in human CX₃CR1-mediated macrophage dysregulation are associated with the worsening of hearing loss and cochlear degeneration after noise trauma: a study in a humanized mouse model.","authors":"Dinesh Y Gawande, Sree Varshini Murali, Shriti S Thakur, Savlatjon Rahmatulloev, Emma J Nicolaisen, Lyudmila Batalkina, Astrid E Cardona, Tejbeer Kaur","doi":"10.1186/s12974-025-03524-1","DOIUrl":"10.1186/s12974-025-03524-1","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Sensorineural hearing loss (SNHL) is characterized by cochlear inflammation, macrophage activation, and degeneration of hair cells, synapses, and neurons. Macrophage-mediated inflammation in the damaged cochlea is regulated via CX3CR1-CX3CL1 signaling, where the fractalkine ligand CX3CL1 serves as a chemotactic and calming signal for macrophage activation. Furthermore, disrupted CX3CR1-CX3CL1 signaling in CX3CR1-KO and CX3CL1-KO mice leads to reduced macrophage numbers, exacerbated inflammation, and loss of hair cells, ribbon synapses, and neurons in the damaged cochlea. Notably, ~ 25% of the human population carries single-nucleotide polymorphisms (SNPs) in the CX3CR1 gene, CX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt;, which results in a receptor with lower binding affinity for CX3CL1, while most individuals carry the common wild-type CX3CR1&lt;sup&gt;V249/T280&lt;/sup&gt; allele. Although these polymorphisms are associated with various CNS neurodegenerative disorders, their impact on SNHL, cochlear degeneration and the macrophage response remains largely unknown. Here, we used a humanized mouse model expressing human CX3CR1 SNPs in lieu of its murine counterpart to investigate the effects of I249/M280 polymorphisms on cochlear function and structure following noise trauma. Young CX3CR1 WT, CX3CR1 KO, and human CX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; mice of both sexes were exposed to a noise level of 93 decibel sound pressure for 2 h at an octave band (8-16 kHz). Cochlear function was assessed prior to exposure and at 1 day and 2 weeks postexposure. Also, the densities of inner and outer hair cells, ribbon synapses, and macrophages in Rosenthal's canal were examined after two weeks of exposure and compared among the three genotypes. We found that at 2 weeks postexposure, hearing thresholds were elevated and input‒output function was impaired in hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; and CX3CR1 KO, whereas mice carrying WT alleles showed functional recovery. A significant synaptic loss (~ 30%) in hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; and CX3CR1 KO mice was observed relative to that in WT, which exhibited synaptic repair. hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; resulted in a ~ 17% loss of outer hair cells, which correlated with reduced otoacoustic emissions in the basal cochlear region. Noise led to increased macrophage numbers in the spiral ganglion and lateral wall of the WT; however, this response was attenuated in the CX3CR1 KO and hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; strains. Additionally, macrophages from CX3CR1 KO and hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; mice presented altered morphology, increased CD68 expression, and inflammation. Compared with those of mice carrying the CX3CR1 WT or KO allele, young hCX3CR1&lt;sup&gt;I249/M280&lt;/sup&gt; mice fostered under ambient noise presented early elevations in hearing thresholds at basal frequencies. Together, these findings reveal that human CX3CR1 variant-mediated macrophage dysregulation strongly correlates with worsening of hearing loss and cochlear degeneration after noise trauma. Our wor","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"204"},"PeriodicalIF":10.1,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cystatin F-a key player in central nervous system disease.","authors":"Yi-Ting Wang, Qiang Li, Jun-Chao Liu, Chen Chen, He-Xuan Ding, Xu Zha, Ke Zhang","doi":"10.1186/s12974-025-03526-z","DOIUrl":"10.1186/s12974-025-03526-z","url":null,"abstract":"<p><p>Cystatin F is an endogenous cysteine protease inhibitor that belongs to the type II cystatin family. It has several unique characteristic structures that determine some of its specific functions. Cystatin F is expressed predominantly in peripheral immune cells and in the microglia of the central nervous system (CNS). Under physiological conditions, the expression of cystatin F in the CNS is minimal. However, emerging evidence suggests that it is significantly upregulated in several CNS diseases. Intriguingly, the role of cystatin F differs across disease contexts-serving a neuroprotective function while promoting pathological progression. Moreover, its function may shift across different pathological stages within the same disorder, reflecting a multifaceted pathophysiology. Cystatin F primarily acts by modulating neuroinflammation, clearing debris, and orchestrating immune responses via its selective expression in disease-associated microglia. As a vital player in CNS diseases, various intervention strategies targeting cystatin F have been proposed, including receptor-interacting protein kinase 1 pathway inhibition, miRNA targeting, mRNA stabilization, necroptosis inhibition, transcriptional regulation and upstream pathway modulation. Several approaches have yielded encouraging results in preclinical models, underscoring the therapeutic potential of modulating cystatin F activity. This review provides a comprehensive overview of the structural features, biological functions, and diverse roles of cystatin F in CNS diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, stroke, Aicardi-Goutières syndrome, prion disease, and glioblastoma. Recent advances in therapeutic interventions focusing on cystatin F have been critically assessed, and key challenges related to clinical translation are outlined, offering new perspectives on therapeutic directions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"203"},"PeriodicalIF":10.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of astrocyte signaling leads to sex-specific changes in microglia phenotypes in a diet-based model of cerebral small vessel disease.","authors":"Jenna L Gollihue, Khine Zin Aung, Colin B Rogers, Leopoldine B Galopin, Nicholas A Wright, Pradoldej Sompol, Erica M Weekman, Yuriko Katsumata, Josh M Morganti, Christopher M Norris","doi":"10.1186/s12974-025-03523-2","DOIUrl":"10.1186/s12974-025-03523-2","url":null,"abstract":"<p><p>Hyperhomocysteinemia (HHcy)-inducing diets recapitulate cerebral small vessel disease phenotypes in mice including cerebrovascular pathology/dysfunction, neuroinflammation, synaptic deficits, and cognitive decline. We recently showed that astrocyte signaling through calcineurin(CN)/nuclear factor of activated T cells (NFATs) plays a causative role in these phenotypes. Here, we assessed the impact of astrocytic signaling on microglia, which set the inflammatory tone in brain. Seven-to-eight-week-old male and female C57BL/6 J mice received intrahippocampal injections of adeno-associated virus (AAV) expressing EGFP (AAV2/5-Gfa2-EGFP) or AAV expressing the NFAT inhibitor VIVIT (i.e., AAV2/5-Gfa2-VIVIT-EGFP). Mice were then fed with control chow (CT) or B-vitamin-deficient chow for 12 weeks to induce HHcy. Immunohistochemistry and Western blot analyses suggested that expression of the homeostatic microglial marker, P2RY12, responded differently to AAV treatments depending on diet and sex. We next conducted single-cell RNA sequencing (scRNA-seq) to determine if microglial genes and/or clustering patterns were differentially sensitive to diet and AAV, depending on sex. In males, disease-associated microglial genes and subclusters were overrepresented in HHcy-treated mice, while VIVIT promoted the appearance of homeostatic microglial genes and clusters. In contrast, microglial genes in females were less sensitive to diet and AAV treatments, though disease-like patterns were also observed in the HHcy condition. Very few of the HHcy-sensitive microglial genes in females were affected by VIVIT. Though based on small sample sizes, the results suggest a sexually dimorphic influence of astrocyte signaling on microglial transcriptional phenotypes in the context of HHcy and small cerebral vessel disease. However, these interpretations will need to be bolstered with additional biological replicates and more stringent statistical analyses.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"202"},"PeriodicalIF":10.1,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRTH2 is critical for IL-1β-producing B cells during experimental autoimmune encephalomyelitis in mice via p38 signaling.","authors":"Jiao Liu, Bei Wang, Chunyan Wu, Ting Wang, Jie Zhou, Yujun Shen, Ying Yu, Shengkai Zuo","doi":"10.1186/s12974-025-03513-4","DOIUrl":"10.1186/s12974-025-03513-4","url":null,"abstract":"<p><p>B cells play a critical role in the pathogenesis of autoimmune inflammatory diseases such as multiple sclerosis (MS). As a receptor of prostaglandin D₂, chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) is known to be involved in Th2 cell activation, but its function in B lymphocytes is unclear. Here, we show that CRTH2 is critical for an IL-1β-producing B cell subset. Mice with B-cell-specific deletion of Crth2 exhibit reduced numbers of IL-1β-producing B cells, resulting in amelioration of experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS. Compared to wild-type B cells, adoptive transfer of Crth2-deficient B cells attenuates EAE disease severity in B-cell-deficient recipient mice. The IL-1β-producing B cell subpopulation was mainly transitional type 2 B cells identified by flow cytometry and single cell sequencing. Mechanically, CRTH2 promotes IL-1β production in B cells through p38 signaling, and pharmacological inhibition of p38 attenuates EAE disease severity in DK-PGD₂-treated mice. Taken together, our results reveal a key function of CRTH2 in driving IL-1β expression in B cells and in controlling their pathogenic activity in autoimmune diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"201"},"PeriodicalIF":10.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal accumulation of glial activation measured by TSPO-PET predicts later brain atrophy in multiple sclerosis.","authors":"Nylund Marjo, Lehto Jussi, Matilainen Markus, Rajander Johan, Wahlroos Saara, Sucksdorff Marcus, Kuhlmann Tanja, Airas Laura","doi":"10.1186/s12974-025-03519-y","DOIUrl":"10.1186/s12974-025-03519-y","url":null,"abstract":"<p><p>In multiple sclerosis (MS), accumulation of disability is driven by CNS-compartmentalized inflammation. This inflammatory process involves activated microglia and astrocytes, which contribute to neuroaxonal damage which in turn accelerates disease progression. Activated glial cells express 18-kDa translocator protein (TSPO), and TSPO-binding radioligands and positron emission tomography (PET) imaging can be used to quantitate glial activation in vivo. The aim of this study was to evaluate the longitudinal evolution of glial activation in untreated cohorts of relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients over one-year follow-up, and to explore how a change in glial activation associates with later imaging and clinical outcomes. Eighteen untreated MS patients (RRMS n = 8, SPMS n = 10) were studied. Expanded disability status scale (EDSS), brain MRI and TSPO-PET scans using [¹¹C]PK11195 were performed at baseline and one year later. Distribution volume ratio (DVR) of [¹¹C]PK11195-binding, and the proportion of TSPO-high voxels at baseline in the normal appearing white matter (NAWM) and other regions of interest were compared to the respective parameters in follow-up scans. Chronic lesions were phenotyped at baseline and at follow-up according to their TSPO-PET-binding patterns, and TSPO-expressing lesions were further characterized using postmortem immunopathological staining. Extended follow-up was obtained after 4-11 years with EDSS available for 18 patients and MR imaging available from 13 patients. TSPO-signal was higher among SPMS compared to RRMS patients at baseline. During one-year follow-up, TSPO uptake remained stable in RRMS patients in all regions of interest. Among the SPMS patients, the proportion of active voxels in the NAWM increased significantly over one-year follow-up. A greater proportion of lesions acquired a rim-active phenotype among SPMS compared to RRMS. According to forward-type stepwise multiple linear regression, change in the proportion of active voxels in the NAWM over one year and baseline body-mass-index were best predictors of later development of brain atrophy (R2 = 0.69). Our study provides novel information about the natural evolution of CNS-compartmentalized inflammation and demonstrates an important link between NAWM TSPO-signal and later adverse outcomes among MS patients, supporting the notion that diffuse glial activation in the NAWM contributes to disease progression.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"200"},"PeriodicalIF":10.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating organophosphate nerve agent, soman (GD), induced long-term neurotoxicity: Saracatinib, a Src Tyrosine Kinase inhibitor, as a potential countermeasure.","authors":"Nyzil Massey, Suraj S Vasanthi, Claire Holtkamp, Christina Meyer, Nikhil S Rao, Luis G Gimenez-Lirola, Chong Wang, Hyunmook Im, Avinash S Bevoor, Sridhar Kannurpatti, Thimmasettappa Thippeswamy","doi":"10.1186/s12974-025-03520-5","DOIUrl":"10.1186/s12974-025-03520-5","url":null,"abstract":"<p><strong>Background: </strong>Acute exposure to soman (GD), an organophosphate nerve agent (OPNA), irreversibly inhibits acetylcholinesterase (AChE), induces seizures, and could be fatal if not treated immediately. Existing medical countermeasures (MCMs- atropine, oximes, and benzodiazepines) mitigate the acute life-threatening cholinergic symptoms but have limited protection against long-term neurological consequences in survivors. This indicates a need for an effective adjunct therapy to mitigate cognitive, behavioral, and brain pathology associated with OPNA exposure. Saracatinib (SAR), a selective Src tyrosine kinase inhibitor, has emerged as a potential candidate, given its protective properties in experimental models of excitotoxicity and neuroinflammation. Here, we evaluate the therapeutic efficacy of SAR in mitigating long-term neurological deficits triggered by acute exposure to soman in a rat model.</p><p><strong>Methods: </strong>Mixed-sex adult Sprague Dawley rats were exposed to soman (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.). Seizure severity was quantified for an hour before administering midazolam (3 mg/kg, i.m.). One-hour post-midazolam, SAR/vehicle was administered orally for a week and in the diet for 17 weeks. After behavioral testing, brain MRI, and EEG acquisition, animals were perfused with 4% paraformaldehyde 18 weeks post-soman. Serum and cerebrospinal fluid were collected for nitrooxidative markers and proinflammatory cytokine. Brains were processed for neuroinflammation and neurodegeneration markers.</p><p><strong>Results: </strong>SAR treatment attenuated the soman-induced anxiety/fear-like behavioral changes and motor impairment and modulated the severity of spontaneous seizures. Despite improved hippocampal functional connectivity (fMRI), SAR did not mitigate soman-induced cognitive deficits at 5-7 weeks. However, 18 weeks of SAR treatment demonstrated anti-inflammatory and antioxidant properties, mitigated reactive gliosis and neurodegeneration, and protected somatostatin inhibitory neurons. The glial scars in the amygdala were reduced in SAR-treated animals compared to the vehicle-treated group.</p><p><strong>Conclusions: </strong>Long-term SAR treatment revealed disease-modifying effects by protecting the brain from soman induced neuroinflammation and neurodegeneration, while also reducing severity of spontaneous seizures. Furthermore, SAR mitigated some soman induced behavioral impairments and brain MRI. These findings highlight the therapeutic potential of Src tyrosine kinase inhibition in soman-induced chronic neurotoxicity.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"199"},"PeriodicalIF":10.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Resistin/TLR4/miR-155-5p axis: a novel signaling pathway in the onset of hypothalamic neuroinflammation.","authors":"Marianne Prévost, Delphine Crépin, Sarah Al Rifai, Ghislaine Poizat, Mélanie Gonçalves, Femke van Barneveld, Rozhina Shadpay, Karim Taouis, Laure Riffault, Yacir Benomar, Mohammed Taouis","doi":"10.1186/s12974-025-03522-3","DOIUrl":"10.1186/s12974-025-03522-3","url":null,"abstract":"<p><p>Hypothalamic neuroinflammation plays a pivotal role in the development of metabolic disorders, contributing to obesity and insulin resistance. Hypercaloric diets rich, particularly high-fat diets (HFDs) induce hypothalamic neuroinflammation, which has been shown to precede peripheral inflammation, even after short-term exposure. However, the mechanisms initiating this central inflammatory response, especially the mediators involved, remain incompletely understood. In this study, we demonstrate that HFD consumption induces the expression of resistin in the hypothalamus. Resistin, an adipokine known to promote inflammation and insulin resistance, was found to modulate the expression profile of microRNAs in the hypothalamus. Notably, intracerebroventricular administration of resistin led to the upregulation of miR-155-5p in a TLR4-dependent manner. Consistently, HFD feeding elevated miR-155-5p levels in the mediobasal hypothalamus. Given the established role of miR-155-5p in promoting macrophage activation in peripheral tissues, we examined its expression in microglial cells. We found that both resistin and palmitate, a saturated fatty acid that mimics HFD-induced metabolic stress, increased miR-155-5p expression in the SIM-A9 microglial cell line, which is derived from mouse cerebral cortex tissue without transformation or artificial immortalization. Our findings reveal a novel resistin/TLR4/miR-155-5p signaling axis that may initiate hypothalamic neuroinflammation. Moreover, we show that the induction of miR-155-5p by resistin depends on activation of the NF-κB, JNK, and p38 MAPK signaling pathways. To further explore this pathway, we performed High-Throughput Sequencing of RNA isolated by Cross-Linking Immunoprecipitation (HITS-CLIP) to identify miR-155-5p targets in SIM-A9 microglia and in the hypothalami of both male and female mice. This approach revealed several common targets, including Quaking and Elmo1, genes implicated in microglial phagocytosis and engulfment. These targets were validated, as transfection of SIM-A9 cells with a miR-155-5p mimic led to downregulation of their expression. Importantly, hypothalamic knockdown of miR-155-5p in both male and female mice improved glucose tolerance and restored Quaking expression in hypothalamic microglia. In conclusion, our data show that HFD promotes hypothalamic resistin expression, which in turn upregulates miR-155-5p via TLR4 and downstream signaling pathways, thereby contributing to hypothalamic neuroinflammation and disrupted glucose homeostasis. We identify the resistin/TLR4/miR-155-5p axis as a novel and critical pathway in the early events of diet-induced neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"198"},"PeriodicalIF":10.1,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydroartemisinin enhances remyelination by switching microglia to the reparative phenotype.","authors":"Li Liu, Lina Yang, Xinke Du, Xiaoxi Kan, Qingsen Ran, Yang Zhang, Manjing Li, Qingwu Liu, Yujie Li, Qing Yang, Ying Chen, Keshan Dong, Xiaoxin Zhu, Qi Li","doi":"10.1186/s12974-025-03510-7","DOIUrl":"10.1186/s12974-025-03510-7","url":null,"abstract":"<p><strong>Background: </strong>Boosting myelin repair is widely recognized as one of the most powerful approaches for demyelinating therapy, essentially contributing to the recovery of neurological functions. Maintaining immune homeostasis in microglia is a prerequisite for creating a reparative environment for myelin. Dihydroartemisinin (DHA) is clinically effective in reshaping immunological status and implies potential in treating demyelinating disease. However, its relevance to pro-remyelination remains unclear.</p><p><strong>Methods: </strong>We first evaluated the effects of DHA on neurofunctional recovery and white matter integrity in chronic experimental autoimmune encephalomyelitis (EAE), an ideal model for secondary progressive multiple sclerosis (SPMS) characterized by remyelination deficiency. Single-cell sequencing and microglial depletion with PLX3397 in vivo were used to reveal the dependency between DHA and microglia. The effect of DHA on the reparative phenotype of microglia, particularly on cholesterol recycling and differentiation of oligodendrocyte progenitor cells (OPCs), was evaluated in microglia-OPCs unit either in vitro or in vivo challenged with myelin debris. Finally, to broaden the clinical application for DHA in myelin repair, it was tested in the cuprizone (CPZ) model which shows remyelination failure, a condition common in various neurodegenerative diseases.</p><p><strong>Results: </strong>We demonstrated for the first time that DHA enhanced white matter integrity and OPCs proliferation and differentiation. This effect is dependent on the transition of microglia to a reparative phenotype. Specifically, DHA increased the secretion of inflammatory-resolving and neurotrophic cytokines. It further functionalized cholesterol recycling and provided metabolic support for myelin regeneration predominantly mediated by liver X receptor (LXR) in microglia. This was evidenced by the promotion of myelin debris uptake, cholesterol catabolism, efflux and transport. Notably, DHA promoted remyelination and neurological functional recovery in CPZ-induced demyelinating model, supporting its potential application in neurodegenerative diseases featuring insufficient remyelination.</p><p><strong>Conclusion: </strong>By highlighting the importance of microglia in promoting myelin regeneration, our study proved DHA as a promising candidate for promoting remyelination.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"197"},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Immune profiling of human vestibular schwannoma secretions identifies TNF-α and TWEAK as cytokines with synergistic potential to impair hearing.","authors":"Sasa Vasilijic, Richard Seist, Zhenzhen Yin, Lei Xu, Konstantina M Stankovic","doi":"10.1186/s12974-025-03484-6","DOIUrl":"10.1186/s12974-025-03484-6","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"196"},"PeriodicalIF":10.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}