bims-microg 2025-02-16 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–02–16
34 papers selected by
Marcus Karlstetter, Universität zu Köln

Macrophages protect against sensory axon loss in peripheral neuropathy.
Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.
Changes in the pH value of the human brain in Alzheimer's disease pathology correlated with CD68-positive microglia: a community-based autopsy study in Beijing, China.
Impairment of DET1 causes neurological defects and lethality in mice and humans.
Multi-functional role of apolipoprotein E in neurodegenerative diseases.
CPT1A ameliorates microglia-induced neuroinflammation via facilitating VDR succinylation.
Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu.
Kinetic changes in microglia-related retinal transcripts in experimental autoimmune uveoretinitis (EAU) of B10.RIII mice.
Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.
Galectin-1 Regulates Inflammatory Responses and Promotes Microglial M2 Polarization in Chronic Migraine.
Microglia TRPC1 SUMOylation drives neuroinflammation after stroke by modulating NLRP3 activity via increasing TRPC1 interaction with ARRB2.
Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.
The effects of hypothalamic microglial activation on ventricular arrhythmias in stress cardiomyopathy.
GDF11 Mitigates Neuropathic Pain via Regulation of Microglial Polarization and Neuroinflammation through TGF-βR1/SMAD2/NF-κB Pathway in Male Mice.
PDE4 inhibition alleviates HMGB1/C1q/C3-mediated excessive phagocytic pruning of synapses by microglia and depressive-like behaviors in mice.
Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids.
CX3CR1-Fractalkine Dysregulation Affects Retinal GFAP Expression, Inflammatory Gene Induction, and LPS Response in a Mouse Model of Hypoxic Retinopathy.
Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia.
Siponimod inhibits microglial inflammasome activation.
ALPK1 signaling pathway activation by HMGB1 drives microglial pyroptosis and ferroptosis and brain injury after acute ischemic stroke.
CX3CL1 Regulation of Gliosis in Neuroinflammatory and Neuroprotective Processes.
A single-cell transcriptome analysis reveals astrocyte heterogeneity and identifies CHI3L1 as a diagnostic biomarker in Parkinson's disease.
Involvement of the STAT3/HIF-1α signaling pathway in α-synuclein-induced ferroptosis.
Zinc regulates microglial polarization and inflammation through IKBα after spinal cord injury and promotes neuronal repair and motor function recovery in mice.
The tumour microenvironment of pilocytic astrocytoma evolves over time via enrichment for microglia.
Experimenters' sex modulates anxiety-like behavior, contextual fear, and microglial oxytocin transcription in mice.
Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation.
Alpha-1 antitrypsin reduces inflammation and vasculopathy in mice with oxygen-induced retinopathy.
Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage.
Pituitary adenylyl cyclase-activating polypeptide modulates the stress response: the involvement of different brain areas and microglia.
Pharmacological Depletion of Microglia Protects Against Alcohol-Induced Corticolimbic Neurodegeneration During Intoxication in Male Rats.
Assessing in-vitro models for microglial development and fetal programming: a critical review.
Understanding the Different Microglia Functional States to Modulate Their Activity in Retinal Degeneration.
Progress in Assessing Retinal Microglia Using Single-Cell RNA Sequencing.

Nature. 2025 Feb 12.

Macrophages protect against sensory axon loss in peripheral neuropathy.

Sara Hakim, Aakanksha Jain, Stuart S Adamson, Veselina Petrova, Jonathan Indajang, Hyoung Woo Kim, Riki Kawaguchi, Qing Wang, Elif S Duran, Drew Nelson, Caitlin A Greene, Jenae Rasmussen, Clifford J Woolf.

Peripheral neuropathy is a common complication of type 2 diabetes, which is strongly associated with obesity1, causing sensory loss and, in some patients, neuropathic pain2,3. Although the onset and progression of diabetic peripheral neuropathy is linked with dyslipidaemia and hyperglycaemia4, the contribution of inflammation to peripheral neuropathy pathogenesis has not been investigated. Here we used a high-fat, high-fructose diet (HFHFD), which induces obesity and prediabetic metabolic changes, to study the onset of peripheral neuropathy. Mice fed the HFHFD developed persistent heat hypoalgesia after 3 months, but a reduction in epidermal skin nerve fibre density manifested only at 6 months. Using single-cell sequencing, we found that CCR2+ macrophages infiltrate the sciatic nerves of HFHFD-fed mice well before axonal degeneration is detectable. These infiltrating macrophages share gene expression similarities with nerve-crush-induced macrophages5 and express neurodegeneration-associated microglial marker genes6, although there is no axon loss or demyelination. Inhibiting the macrophage recruitment by genetically or pharmacologically blocking CCR2 signalling resulted in more severe heat hypoalgesia and accelerated skin denervation, as did deletion of Lgals3, a gene expressed in recruited macrophages. Recruitment of macrophages into the peripheral nerves of obese prediabetic mice is, therefore, neuroprotective, delaying terminal sensory axon degeneration by means of galectin 3. Potentiating and sustaining early neuroprotective immune responses in patients could slow or prevent peripheral neuropathy.

DOI: https://doi.org/10.1038/s41586-024-08535-1
Nat Commun. 2025 Feb 13. 16(1): 1577

Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.

Theo Perochon, Zeljka Krsnik, Marco Massimo, Yana Ruchiy, Alejandro Lastra Romero, Elyas Mohammadi, Xiaofei Li, Katherine R Long, Laura Parkkinen, Klas Blomgren, Thibault Lagache, David A Menassa, David Holcman.

Mapping cellular organization in the developing brain presents significant challenges due to the multidimensional nature of the data, characterized by complex spatial patterns that are difficult to interpret without high-throughput tools. Here, we present DeepCellMap, a deep-learning-assisted tool that integrates multi-scale image processing with advanced spatial and clustering statistics. This pipeline is designed to map microglial organization during normal and pathological brain development and has the potential to be adapted to any cell type. Using DeepCellMap, we capture the morphological diversity of microglia, identify strong coupling between proliferative and phagocytic phenotypes, and show that distinct spatial clusters rarely overlap as human brain development progresses. Additionally, we uncover an association between microglia and blood vessels in fetal brains exposed to maternal SARS-CoV-2. These findings offer insights into whether various microglial phenotypes form networks in the developing brain to occupy space, and in conditions involving haemorrhages, whether microglia respond to, or influence changes in blood vessel integrity. DeepCellMap is available as an open-source software and is a powerful tool for extracting spatial statistics and analyzing cellular organization in large tissue sections, accommodating various imaging modalities. This platform opens new avenues for studying brain development and related pathologies.

DOI: https://doi.org/10.1038/s41467-025-56560-z
Mol Brain. 2025 Feb 10. 18(1): 10

Changes in the pH value of the human brain in Alzheimer's disease pathology correlated with CD68-positive microglia: a community-based autopsy study in Beijing, China.

Xue Wang, Xiangqi Shao, Liang Yu, Jianru Sun, Xiang-Sha Yin, Zhen Chen, Yuanyuan Xu, Naili Wang, Di Zhang, Wenying Qiu, Fan Liu, Chao Ma.

  The microenvironment of the central nervous system is highly complex and plays a crucial role in maintaining the function of neurons, which influences Alzheimer's disease (AD) progression. The pH value of the brain is a critical aspect of the brain microenvironment in regulating various physiological processes. However, the specific mechanisms and role of this mechanism are not yet fully understood. To better understand the relationship between brain pH and AD, we analyzed the brain pH of the frontal lobe and AD pathology scores in postmortem brain samples from 368 donors from the National Human Brain Bank for Development and Function, 96 of whom were diagnosed with AD pathology. Analysis revealed a significant decrease in brain pH in AD patients, which was strongly correlated with β-amyloid plaques and phosphorylated tau proteins. Here, we elucidated the differential protein expression level of CD68-positive microglia between control and AD groups (t = 3.198, df = 20, P = 0.0045), and its protein expression level was correlated negatively with the brain pH value (F = 26.93, p = 0.0006). Our findings revealed that increased activation of CD68-positive microglia and disrupted lysosomal homeostasis in the pathological brain tissue of individuals with AD may lead to a decrease in brain pH.

Keywords:  Alzheimer’s Disease; Human Brain Bank; Microglia; Postmortem brain; pH value

DOI:  https://doi.org/10.1186/s13041-025-01180-3
Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2422631122

Impairment of DET1 causes neurological defects and lethality in mice and humans.

Ozge Karayel, Allison Soung, Hem Gurung, Alexander F Schubert, Susan Klaeger, Marc Kschonsak, Aljazi Al-Maraghi, Ajaz A Bhat, Ammira S Alshabeeb Akil, Debra L Dugger, Joshua D Webster, Dorothy M French, Dhullipala Anand, Naharmal Soni, Khalid A Fakhro, Christopher M Rose, Seth F Harris, Ada Ndoja, Kim Newton, Vishva M Dixit.

  COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous DET1R26W mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1R26W impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for DET1R26W expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of Det1-deficient microglia as compared to WT microglia, indicating that the deleterious effects of the DET1 p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.

Keywords:  COP1; DET1; E3 ligase; neurodevelopment; ubiquitin

DOI:  https://doi.org/10.1073/pnas.2422631122
Front Aging Neurosci. 2025 ;17 1535280

Multi-functional role of apolipoprotein E in neurodegenerative diseases.

Sadequl Islam, Arshad Noorani, Yang Sun, Makoto Michikawa, Kun Zou.

  Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer's disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE's diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE's influence in other neurodegenerative diseases like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington's disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyloid-β (Aβ); amyotrophic lateral sclerosis; apolipoprotein E; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fnagi.2025.1535280
Sci Rep. 2025 Feb 12. 15(1): 5181

CPT1A ameliorates microglia-induced neuroinflammation via facilitating VDR succinylation.

Wenyao Li, Ying Li, Yun Chen, Yan Wang, Lihua Qian.

  Neurodegenerative diseases, characterized by impairments in cognition, memory, and movement, are becoming increasingly prevalent due to population aging, posing a significant threat to public health. Extensive evidence suggests that neuroinflammation, mediated by microglia, plays a crucial role in the development of these diseases. Notably, the vitamin D receptor (VDR) has been shown to regulate microglia activation by controlling the function of neuroprotective vitamin D. This study aims to elucidate the potential of VDR in modulating neuroinflammation. To mimic neuroinflammation, BV2 cells were treated with lipopolysaccharide (LPS) for 12 h. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the release of cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, MCP-1, and TNF-α. Western blot assays were performed to assess relative protein expressions and succinylation modifications. Co-immunoprecipitation (Co-IP) experiments were conducted to determine the interaction between VDR and carnitine palmitoyltransferase 1A (CPT1A). Immunofluorescence staining was used to analyze the localization of VDR, CPT1A, COX-2, and CD11b. Our findings demonstrated that VDR expression was upregulated in BV2 cells exposed to LPS. Ectopic expression of VDR attenuated the inflammatory response and microglia activation. We discovered that carnitine palmitoyltransferase 1A (CPT1A) promoted VDR succinylation. Further investigations revealed that CPT1A enhanced VDR stability by binding to VDR, with lysine K117 being the primary succinylation site. Importantly, depletion of CPT1A abrogated the protective effects of VDR overexpression on microglia-mediated neuroinflammation. Our study highlighted that CPT1A functioned as a suppressor in neuroinflammation by facilitating VDR succinylation, offering potential therapeutic targets for the management of neurodegenerative diseases.

Keywords:  CPT1A; Microglia; Neurodegenerative diseases; Neuroinflammation; Vitamin D receptor

DOI:  https://doi.org/10.1038/s41598-025-88298-5
Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2413484122

Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu.

Hyung Soon Kim, Seung Ah Jee, Ariandokht Einisadr, Yeojin Seo, Hyo Gyeong Seo, Byeong Seong Jang, Hee Hwan Park, Won-Suk Chung, Byung Gon Kim.

  Poststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is considered a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in poststroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on poststroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 d after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of fluorescence-activated single cell sorting (FACS)-sorted CD45low microglia revealed decreased transforming growth factor-β (TGF-β) signaling and proinflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro coculture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings present unique insights into the function of Arg1 in central nervous system injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the poststroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating poststroke inflammation and improving functional recovery.

Keywords:  Arginase-1; functional recovery; infiltrating macrophages; ischemic stroke; microglia

DOI:  https://doi.org/10.1073/pnas.2413484122
J Neuroinflammation. 2025 Feb 10. 22(1): 37

Kinetic changes in microglia-related retinal transcripts in experimental autoimmune uveoretinitis (EAU) of B10.RIII mice.

Maren Kasper, Marcus Karlstetter, Lena Wildschütz, Rebecca Scholz, Martin Busch, Dirk Bauer, Gerd Meyer Zu Hörste, Solon Thanos, Thomas Langmann, Arnd Heiligenhaus.

  In this study the retinal transcriptome was investigated during the development of experimental autoimmune uveoretinitis (EAU) in mice. EAU was induced by immunizing B10.RIII mice with human interphotoreceptor retinoid binding protein (hIRBP) 161-180 peptide. Genome-wide transcriptional profiles of EAU (day 7, 14 or 21 after immunization) and of control retinas were generated using DNA-microarrays and bioinformatic data mining. Microglia-associated transcripts were identified. Quantitative real-time polymerase chain reaction was performed to validate the expression of differentially expressed genes. Retinal transcript validation revealed that complement and interferon-related pathways, as well as gene clusters specific for antigen-processing and -presentation, and immunosuppression are involved during the course of the disease. Immunofluorescence analysis confirm that upregulated transcripts in EAU are also expressed by retinal microglia. Furthermore, the heterogenous expression patterns observed in retinal microglia, suggests the presence of different subpopulations of retinal microglia in EAU. This study expands our knowledge of the local immune processes involved in EAU pathology.

Keywords:  Autoimmune uveitis; EAU; Microglia; Retinal transcriptome

DOI:  https://doi.org/10.1186/s12974-025-03358-x
Mol Neurobiol. 2025 Feb 14.

Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.

Gunel Ayyubova, Leelavathi N Madhu.

  The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.

Keywords:  Alzheimer’s disease; Autophagy; Microglia; Mitophagy; NLRP3 inflammasome

DOI:  https://doi.org/10.1007/s12035-025-04758-z
Eur J Neurosci. 2025 Feb;61(3): e70010

Galectin-1 Regulates Inflammatory Responses and Promotes Microglial M2 Polarization in Chronic Migraine.

Yue Xiao, Wei Han, Ming Yu, Jianzhong Jiang, Yuanyuan Zhu.

  Chronic migraine (CM) is a severe and debilitating neurological disorder with an unclear pathophysiology. Galectin-1, a β-galactoside-binding protein, is known for its anti-inflammatory and immune-regulatory effects in various inflammation-related diseases. However, its role in CM has not been fully elucidated. In this study, we analysed data from CM patients and employed a nitroglycerin-induced CM mouse model to explore the potential role of galectin-1. Serum galectin-1 levels were significantly lower in CM patients compared with healthy controls. Additionally, galectin-1 levels were negatively correlated with Visual Analogue Scale (VAS) and Headache Impact Test (HIT-6) scores. CM patients also exhibited elevated levels of IL-6 and TNF-α and reduced levels of IL-10. Notably, galectin-1 levels were inversely correlated with IL-6 and TNF-α and positively correlated with IL-10. In the CM mouse model, galectin-1 expression was significantly reduced in the spinal trigeminal nucleus caudalis (Sp5C) region. Supplementation with galectin-1 significantly increased paw and periorbital mechanical thresholds and reduced light aversion and anxiety-like behaviours. Moreover, galectin-1 enhanced microglial morphology, promoted M2 polarization, reduced the expression of pro-inflammatory factors IL-6 and TNF-α and increased levels of the anti-inflammatory cytokine IL-10. Mechanistically, the effects of galectin-1 on microglia may involve the activation of the PI3K/AKT signalling pathway, as evidenced by increased phosphorylation of PI3K and AKT. In summary, our study demonstrates that galectin-1 plays a crucial role in the pathogenesis of chronic migraine. Exogenous supplementation of galectin-1 effectively alleviates migraine symptoms and promotes microglial M2 polarization, suggesting that galectin-1 may represent a novel therapeutic target for CM.

Keywords:  chronic migraine; galectin‐1; inflammation; microglia

DOI:  https://doi.org/10.1111/ejn.70010
Neurobiol Dis. 2025 Feb 06. pii: S0969-9961(25)00049-X. [Epub ahead of print]206 106833

Microglia TRPC1 SUMOylation drives neuroinflammation after stroke by modulating NLRP3 activity via increasing TRPC1 interaction with ARRB2.

Huinan Zhang, Xinzhe Du, Tian Gao, Xing Wang, Huifeng Zhang, Manyang Yu, Jing Huang.

  Microglial canonical transient receptor potential channel 1 (TRPC1) has been proposed to influence neuroinflammation after cerebral ischemia and reperfusion injury (CIRI), however, the underlying mechanism remains poorly understood. This study demonstrates that TRPC1 is modified by small ubiquitin-related modifier (SUMO)ylation. Our findings suggest a notable increase in microglial TRPC1 SUMOylation within both the middle cerebral artery occlusion reperfusion (MCAO/R) model and the in vitro oxygen-glucose deprivation/regeneration model. Mice with a loss of TRPC1 SUMOylation in microglia exhibited improved stroke outcomes including reduced behavior deficits, infarct volume, blood brain barrier damage as well as neuronal apoptosis. Mechanistically, SUMOylation of microglial TRPC1 exacerbated neutrophil infiltration into the peri-infarct area. Additionally, SUMOylated TRPC1 activates the Nod-like receptor protein (NLRP) 3 signaling pathway in microglia and stimulates multiple CC-chemokine ligands and C-X-C motif ligand chemokines after MCAO/R. SUMOylated TRPC1 facilitates the interaction between TRPC1 and β-arrestin2 (ARRB2), a negative regulator of NLRP3 inflammasome, which disrupts the NLPR3/ARRB2 complex and stimulates the activation of the NLPR3 signaling pathway. Furthermore, ARRB2 directly binds to the residues 46 to 61 of TRPC1 N terminus, which is enhanced by TRPC1 SUMOylation. Collectively, our findings demonstrate a previously unidentified mechanism by which SUMOylated TRPC1 in microglia regulates leukocyte infiltration after stroke, suggesting that the inhibition of microglial TRPC1 SUMOylation may provide therapeutic benefits for CIRI.

Keywords:  ARRB2; Microglia; NLRP3; SUMOylation; Stroke; TRPC1

DOI:  https://doi.org/10.1016/j.nbd.2025.106833
J Exp Med. 2025 Apr 07. pii: e20230173. [Epub ahead of print]222(4):

Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.

Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna.

Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.

DOI: https://doi.org/10.1084/jem.20230173
J Geriatr Cardiol. 2024 Dec 28. 21(12): 1119-1132

The effects of hypothalamic microglial activation on ventricular arrhythmias in stress cardiomyopathy.

Peng-Qi Lin, Quan-Wei Pei, Bin Li, Jie-Mei Yang, Li-Na Zou, De-Zhan Su, Jun-Pei Zhang, Hong-Peng Yin, Mbabazi Nadine, Jun-Jie Yang, Nevzorova Vera A, Khan Musawir Abbas, Zhao-Lei Jiang, Jing-Jie Li, De-Chun Yin.

Background: Stress cardiomyopathy (SCM) currently has a high incidence in older adults, and the theories regarding its causes include "catecholamine myocardial toxicity" and "sympathetic hyperactivation". However, the role of the central nervous system in the pathogenesis of SCM remains unknown. We investigated the role of microglia activation in the paraventricular hypothalamic nucleus (PVN) in the development of SCM.
Methods: An SCM model was created using male Sprague-Dawley (SD) rats, immobilized for 6 h every day for a week. Electrocardiogram, cardiac electrophysiology, and echocardiography examinations were performed to verify the changes in cardiac structure and function in rats with SCM. RNA sequencing was used to explore the changes in the hypothalamus during SCM. In addition, brain and heart tissues were collected to detect microglial activation and sympathetic activity.
Results: The main findings were as follows: (1) immobilization stress successfully induced SCM in SD rats; (2) microglia were significantly activated in the hypothalamus, as evidenced by cytosol thickening, increases in the number of microglial branches, and microglia enriched in the PVN; (3) in SCM, the microglia in the PVN exhibited increased central and peripheral cardiac sympathetic activity and increased the expression of neuroinflammatory factors; and (4) it is possible that inhibiting microglial activation could suppress the sympathetic activity of the central nervous system and heart and increase cardiac electrical stability in SCM rats.
Conclusions: SCM was induced in SD rats by immobilization stress, acting through the activation of the hypothalamic microglia. The activated microglia were specifically enriched in the PVN, increasing the activity of the central and peripheral sympathetic nervous systems by regulating the expression of neuro-inflammatory factors, mediating dysfunction of the left ventricle, and increasing the susceptibility to ventricular arrhythmias.

DOI: https://doi.org/10.26599/1671-5411.2024.12.002
J Neuroimmune Pharmacol. 2025 Feb 12. 20(1): 20

GDF11 Mitigates Neuropathic Pain via Regulation of Microglial Polarization and Neuroinflammation through TGF-βR1/SMAD2/NF-κB Pathway in Male Mice.

Tianzhu Liu, Longqing Zhang.

  Spinal microglial activation and the polarization towards the M1 phenotype are implicated in the pathological process of neuropathic pain. Extensive research has elucidated that growth and differentiation factor 11 (GDF11), a constituent of the transforming growth factor-β (TGF-β) superfamily, exerts inhibitory effects on macrophage activation and mitigates inflammatory responses via the activation of TGF-β receptor type I (TGF-βR1). Nonetheless, the influence of GDF11 on spinal microglial polarization and its role in neuropathic pain remains to be ascertained. In the present investigation, a neuropathic pain model was induced via a spared nerve injury (SNI) procedure on the sciatic nerve in male mice. The impact of GDF11 on microglial polarization and neuropathic pain in SNI-subjected mice was evaluated through pain behavior assessments, WB, IF, qRT-PCR, and ELISA. Our findings revealed a significant downregulation of spinal GDF11 and TGF-βR1 expression levels in microglia of mice subjected to SNI. Furthermore, GDF11 treatment notably reversed the mechanical allodynia and thermal hyperalgesia, inhibited M1 microglial polarization, and attenuated neuroinflammatory processes by modulating the SMAD2/NF-κB in SNI mice. However, the analgesic effects of GDF11 on pain hypersensitivity and its modulatory influence on spinal microglial polarization were abrogated by the application of a specific antagonist of TGF-βR1, or the TGF-βR1 siRNA. In summary, GDF11 effectively ameliorated mechanical allodynia and thermal hyperalgesia, suppressed M1 microglial polarization, and alleviated neuroinflammation via the regulation of the TGF-βR1/SMAD2/NF-κB pathway in mice with SNI. These findings suggest that GDF11 holds promise as a therapeutic modality for the management of neuropathic pain.

Keywords:  GDF11; Microglial polarization; Neuroinflammation; Neuropathic pain; Spinal cord

DOI:  https://doi.org/10.1007/s11481-025-10172-y
Brain Behav Immun. 2025 Feb 11. pii: S0889-1591(25)00047-9. [Epub ahead of print]

PDE4 inhibition alleviates HMGB1/C1q/C3-mediated excessive phagocytic pruning of synapses by microglia and depressive-like behaviors in mice.

Qian Zhao, Chunyuan Zeng, Fulan Luo, Zihong Xian, Huizhen Wen, Xingxing Tu, Rifang Yang, Yijun Sun, Xiangling Zheng, Jiangping Xu, Haitao Wang.

  Microglial activation and complement-mediated synaptic pruning are involved in depression development. We previously found that the inhibition of phosphodiesterase 4 (PDE4) inhibits microglial activation and increases synaptic plasticity. However, the role of PDE4 in microglia phagocytosis and complement-mediated synaptic pruning during depression remains unclear. Here, we investigated the effect of PDE4 on the expression of complement component 1q (C1q) and C3. We also designed and synthesized a novel PDE4 inhibitor LS21013A-06 (A06), and examined whether A06 exerts antidepressant-like effects by regulating microglia phagocytosis and complement-mediated synaptic pruning. We found that treatment with high-mobility group box-1 (HMGB1) triggered an inflammatory response, enhanced levels of complement component 1q (C1q) and C3, and promoted microglial phagocytosis both in vitro and in vivo. Notably, PDE4B knockdown reduced the levels of HMGB1, C1q, and C3 in lipopolysaccharide (LPS)-treated BV2 cells. Inhibition of PDE4 by A06 reduced the levels of HMGB1, suppressed neuroinflammation and microglial phagocytosis. In addition, A06 alleviated LPS-induced depressive-like behaviors in mice, reduced the levels of HMGB1, C1q, and C3 in the hippocampus, elevated the level of postsynaptic density protein-95, and reduced excessive microglial phagocytosis and engulfment of synapses. Moreover, C1q overexpression inhibited the effects of A06 on microglial activation and synaptic pruning. In conclusion, we demonstrated for the first time that PDE4 regulates the expression of C1q/C3, and A06 reduces microglial activation and ameliorates depressive-like behavior in mice. This mechanism involves complement C1q/C3-mediated excessive microglia phagocytosis and synaptic pruning.

Keywords:  C1q/C3; Complement; HMGB1; Microglial activation; PDE4; Synaptic pruning

DOI:  https://doi.org/10.1016/j.bbi.2025.02.007
J Neuroinflammation. 2025 Feb 10. 22(1): 36

Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids.

Srinivas D Narasipura, Janet P Zayas, Michelle K Ash, Anjelica F Reyes, Tanner Shull, Stephanie Gambut, James L A Szczerkowski, Charia McKee, Jeffrey R Schneider, Ramon Lorenzo-Redondo, Lena Al-Harthi, João I Mamede.

  Cerebral organoids (COs) are valuable tools for studying the intricate interplay between glial cells and neurons in brain development and disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors and inducing pluripotent stem cells. This approach allowed for the differentiation of microglia within the organoids concomitantly with the neuronal progenitors. Compared with conventional COs, CO-iMs were more efficient at generating CD45+/CD11b+/Iba-1+ microglia and presented a physiologically relevant proportion of microglia (~ 7%). CO-iMs presented substantially increased expression of microglial homeostatic and sensome markers as well as markers for the complement cascade. CO-iMs are susceptible to HIV infection, resulting in a significant increase in several pro-inflammatory cytokines/chemokines, which are abrogated by the addition of antiretrovirals. Thus, CO-iM is a robust model for deciphering neuropathogenesis, neuroinflammation, and viral infections of brain cells in a 3D culture system.

Keywords:  Cerebral organoids; HIV; HPC; IPSC; Microglia; Neuroinflammation; Neuropathogenesis

DOI:  https://doi.org/10.1186/s12974-025-03353-2
Int J Mol Sci. 2025 Jan 28. pii: 1131. [Epub ahead of print]26(3):

CX3CR1-Fractalkine Dysregulation Affects Retinal GFAP Expression, Inflammatory Gene Induction, and LPS Response in a Mouse Model of Hypoxic Retinopathy.

Colin Rorex, Sandra M Cardona, Kaira A Church, Derek Rodriguez, Difernando Vanegas, Reina A Saldivar, Amira El-Sheikh, Yufeng Wang, Stefka Gyoneva, Anne C Cotleur, Astrid E Cardona.

  Diabetic retinopathy (DR) causes vision loss due to sustained inflammation and vascular damage. The vascular damage is evident by fibrinogen leakage, angiogenesis, and hypoxia. Neuronal regulation of microglia via the CX3CL1 (Fractalkine or FKN)-CX3CR1 pathway plays a significant role in retinal pathology. Defects in FKN or CX3CR1 exacerbate inflammation, vascular damage, and vision impairment. However, the contribution of hypoxic astrocytes to the pathological process of DR is unclear. A hypoxic model (7 days of systemic 7.5% O2) was utilized to induce retinal damage in adult mice in the absence of systemic inflammatory signals. This model induced vascular and microglial responses similar to 10 weeks of STZ-induced hyperglycemia. The goal of this study is to characterize retinal damage in WT and mice with defects in the FKN-CX3CR1 signaling axis and hence assess the impact of the microglial inflammatory responses to hypoxic retinopathy. Tissues were analyzed by immunostaining, RNA sequencing, and cytokine quantification. We found that CX3CR1 deficiency in hypoxic animals induced reactive astrogliosis and that Müller glial responses to hypoxia and systemic inflammation were dependent on FKN signaling. Exacerbated microglial reactivity to hypoxic conditions significantly altered the expression of HIF transcripts. Microglial dysregulation was found to reduce the anti-inflammatory response to hypoxic conditions, downregulate hypoxia-responsive gene expression, and restrained LPS-induced inflammatory responses. We found that microglia dysregulation alters the hypoxic response by inhibiting the upregulation of HIF2α/3α, increasing CD31 immunoreactivity, and altering the expression of ECM-associated transcripts such as type I, III, and XVIII collagens to hypoxic conditions.

Keywords:  Müller glia; astrocytes; diabetic retinopathy; fibrinogen; hypoxia; inflammation; microglia

DOI:  https://doi.org/10.3390/ijms26031131
Cells. 2025 Feb 06. pii: 235. [Epub ahead of print]14(3):

Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia.

Fergan Imbert, Dianne Langford.

  SUMOylation, the post-translational modification of proteins by small ubiquitin-like modifiers, plays a critical role in regulating various cellular processes, including innate immunity. This modification is essential for modulating immune responses and influencing signaling pathways that govern the activation and function of immune cells. Recent studies suggest that SUMOylation also contributes to the pathophysiology of central nervous system (CNS) viral infections, where it contributes to the host response and viral replication dynamics. Here, we explore the multifaceted role of SUMOylation in innate immune signaling and its implications for viral infections within the CNS. Notably, we present novel proteomic analyses aimed at elucidating the role of the small ubiquitin-related modifier (SUMO) in human immunodeficiency virus (HIV) latency in microglial cells. Our findings indicate that SUMOylation may regulate key proteins involved in maintaining viral latency, suggesting a potential mechanism by which HIV evades immune detection in the CNS. By integrating insights from proteomics with functional studies, we anticipate these findings to be the groundwork for future studies on HIV-host interactions and the mechanisms that underlie SUMOylation during latent and productive infection.

Keywords:  CNS; HIV; SUMOylation; microglia; post-translational modifications

DOI:  https://doi.org/10.3390/cells14030235
Neurosci Res. 2025 Feb 05. pii: S0168-0102(25)00028-8. [Epub ahead of print]

Siponimod inhibits microglial inflammasome activation.

Hiroyasu Komiya, Hideyuki Takeuchi, Akihiro Ogasawara, Yuki Ogawa, Shun Kubota, Shunta Hashiguchi, Keita Takahashi, Misako Kunii, Kenichi Tanaka, Mikiko Tada, Hiroshi Doi, Fumiaki Tanaka.

  Siponimod is the first oral drug approved for active secondary progressive multiple sclerosis. It acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) through S1P1 internalization, and also serves an agonist of S1P5; however, the detailed mechanisms of its therapeutic effects on glial cells have yet to be elucidated. In this study, we investigated the anti-inflammatory mechanism of siponimod in microglia. Pretreatment with either siponimod or the S1P1 antagonist W146 significantly suppressed the production of interleukin-1β in activated microglia stimulated with lipopolysaccharide plus nigericin, an inflammasome activator. Furthermore, siponimod treatment reduced the protein levels of cleaved caspase-1 and inhibited the formation of aggregates of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC specks) in microglia. Our data indicate that siponimod achieves its anti-inflammatory effects by inhibiting inflammasome activation in microglia via S1P1 antagonism. This process is inferred to play a crucial role in mitigating the secondary progression of multiple sclerosis, where microglial activation in the gray matter is considered a key pathological factor.

Keywords:  Cytokine; Inflammasome; Microglia; Multiple sclerosis; Siponimod; Sphingosine-1-phosphate receptor 1

DOI:  https://doi.org/10.1016/j.neures.2025.02.002
Int Immunopharmacol. 2025 Feb 10. pii: S1567-5769(25)00219-X. [Epub ahead of print]149 114229

ALPK1 signaling pathway activation by HMGB1 drives microglial pyroptosis and ferroptosis and brain injury after acute ischemic stroke.

Ou Du, Ya-Ling Yan, Han-Yinan Yang, Yu-Xin Yang, An-Guo Wu, Yin-Kun Guo, Kuan Li, Gan Qiao, Jun-Rong Du, Fang-Yi Long.

  Pyroptosis and ferroptosis emerge as remarkable contributors to neuronal death and inflammation following ischemic stroke. High mobility group box 1 (HMGB1), a principal damage-associated molecular pattern (DAMP), is implicated in pyroptosis and ferroptosis post-stroke. Our previous research has demonstrated that alpha kinase 1 (ALPK1), a novel cytoplasmic pattern recognition receptor (PRR), plays an important role in mediating inflammatory damage following ischemic stroke. However, the interaction between ALPK1 and HMGB1, and their combined impact on pyroptosis and ferroptosis post-ischemic stroke remain unexplored, which is what this study aims to investigate. Initially, we observed that ALPK1 ablation attenuated ischemic brain injury of transient middle cerebral artery occlusion (tMCAO) mice. Moreover, recombinant HMGB1 (rHMGB1) stimulation induced the greatest upregulation of ALPK1 expression in microglia compared to astrocytes and neurons. Further investigation using co-immunofluorescence, co-immunoprecipitation, pull-down assay, and molecular docking revealed an interaction between HMGB1 and ALPK1. Additionally, the exacerbation of ischemic brain injury and the induction of microglial pyroptosis and ferroptosis by rHMGB1 treatment in tMCAO mice were significantly mitigated through ALPK1 deficiency by inhibiting the NLRP3/Caspase-1/GSDMD and JAK2/STAT3 signaling pathways. The inhibitory effects of ALPK1 deficiency on pyroptosis and ferroptosis induced by rHMGB1 in microglial cells were further substantiated. Finally, glycyrrhizic acid (GA), an inhibitor of HMGB1, exhibited significant neuroprotective effects in both tMCAO mice and BV2 cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R) by downregulating ALPK1 expression and inhibiting microglial pyroptosis and ferroptosis. Collectively, these findings suggest that HMGB1 may interact with ALPK1 to drive microglial pyroptosis and ferroptosis via the activation of the ALPK1/NF-κB/NLRP3/GSDMD and JAK2/STAT3 signaling pathways, thereby exacerbating brain injury following acute ischemic stroke.

Keywords:  Acute ischemic stroke; Alpha-kinase 1 (ALPK1); DAMPs/PRRs; Ferroptosis; HMGB1; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2025.114229
Int J Mol Sci. 2025 Jan 23. pii: 959. [Epub ahead of print]26(3):

CX3CL1 Regulation of Gliosis in Neuroinflammatory and Neuroprotective Processes.

Irene L Gutiérrez, David Martín-Hernández, Karina S MacDowell, Borja García-Bueno, Javier R Caso, Juan C Leza, José L M Madrigal.

  Among the different chemokines, C-X3-C motif chemokine ligand 1 or CX3CL1, also named fractalkine, is one of the most interesting due to its characteristics, including its unique structure, not shared by any other chemokine, and its ability to function both in a membrane-bound form and in a soluble form, among others. However, undoubtedly, its most relevant characteristic from the neuroscientific point of view is its role as a messenger used by neurons to communicate with microglia. The study of the interaction between both cell types and the key role that CX3CL1 seems to play has facilitated the identification of CX3CL1 as a crucial modulator of microglial activation and a promising target in the fight against neuroinflammation. As a result, numerous studies have contributed to elucidate the involvement of CX3CL1 and its specific receptor CCX3CR1 in the progression of different neuroinflammatory and neurodegenerative processes, with Alzheimer's and Parkinson's diseases being the most studied ones. However, the different animal and cellular models used to reproduce the pathological conditions to be analyzed, as well as the difficulties inherent to studies performed on human samples, have hindered the collection of compatible results in many cases. In this review, we summarize some of the most relevant data describing the alterations found for the CX3CL1/CX3CR1 signaling axis in different neurodegenerative conditions in which neuroinflammation is known to play a relevant role.

Keywords:  CX3CL1; CX3CR1; chemokines; fractalkine; microglia; neurodegeneration; neuroinflammation; neurons

DOI:  https://doi.org/10.3390/ijms26030959
Heliyon. 2025 Feb 15. 11(3): e42051

A single-cell transcriptome analysis reveals astrocyte heterogeneity and identifies CHI3L1 as a diagnostic biomarker in Parkinson's disease.

Zhongying Gong, Dan Guo, Yufeng Lin, Zhiwei Liu, Mengdi Lv, Xinxin Liu, Yang Yao, Sijia Wang, Yuan Wang, Zhiyun Wang.

   Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by motor and non-motor symptoms. It has been reported that astrocytes play a critical role in the pathogenesis and progression of PD. Here, we aimed to identify the heterogeneity of astrocytes and investigate genes associated with astrocyte differentiation trajectories in PD.
Methods: The single-cell transcriptomic profiles of PD samples were collected from the GEO database. We have identified subsets of astrocytes and analyzed their functions. The differentiation trajectory of astrocyte subtypes was explored using Monocle2. Inflammatory response scores were determined using AUCell. The levels of CHI3L1 mRNA and protein expressions in astrocytes were analyzed using qRT-PCR and Western Blot assay, respectively.
Results: We characterized seven cell types within the substantia nigra region of both PD and normal samples. Our analysis revealed that astrocytes comprised the second-highest proportion of cell types. Additionally, we identified three distinct subpopulations of astrocytes: Astro-C0, Astro-C1, and Astro-C2. Notably, Astro-C0 was associated with inflammatory signaling pathways. Trajectory analysis indicated that Astro-C0 occupies an intermediate stage of differentiation. The astrocyte-related gene CHI3L1 was found to be highly expressed in the Astro-C0 subpopulation. Furthermore, we observed increased levels of CHI3L1 mRNA and protein in LPS-induced astrocytes. Astrocytes exhibiting elevated CHI3L1 levels demonstrated interactions with microglia in PD patients. Lastly, we discovered that CHI3L1 was significantly overexpressed in PD patients and exhibited strong diagnostic potential for the disease.
Conclusion: This study clarified the heterogeneity of astrocytes in PD based on the single-cell transcriptomic profiles and found that CHI3L1 may be a diagnostic biomarker for PD.

Keywords:  Astrocytes; CHI3L1; Diagnostic biomarker; Inflammation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.heliyon.2025.e42051
Biochem Biophys Res Commun. 2025 Feb 01. pii: S0006-291X(25)00133-0. [Epub ahead of print]752 151419

Involvement of the STAT3/HIF-1α signaling pathway in α-synuclein-induced ferroptosis.

Han Zhang, Jieli Zhang, Xiuna Jing, Kaixun Huang, Ying Chen, Qingyu Shen, Enxiang Tao, Danyu Lin.

  Oligomeric α-synuclein (α-syn) aggregates, which are a critical pathological feature of Parkinson's disease (PD), can induce neuroinflammation and neurodegeneration. Our previous study revealed a decrease in IL6ST/JAK2/STAT3/HIF-1α pathway in α-syn-induced microglia. As we all know, the JAK2/STAT3 signaling pathway is essential for modulating inflammation, controlling cell growth and exhibiting antiapoptotic responses. However, the precise role of STAT3/HIF-1α in the ferroptosis of α-syn pathology has not been identified in vivo. In this study, above all, we successfully established α-syn-induced mouse models of Parkinson's disease. Our immunohistochemistry results demonstrated that α-syn could activate IL6ST/STAT3/HIF-1α pathway in a model of α-syn-induced PD. We further conducted transcriptomic analysis on a mouse model of α-syn-induced PD, and GSEA revealed an association with ferroptosis. Consequently, we focused on investigating how α-syn might regulate the transcriptional activation of HSPB1. In conclusion, we determined the relationship between ferroptosis and the STAT3/HIF-1α pathway in α-syn-related pathology in vivo. Oligomeric α-syn could induce ferroptosis via the STAT3/HIF-1α signaling pathway.

Keywords:  Ferroptosis; Parkinson's disease; STAT3/HIF-1α; Transcriptomics; α-synuclein

DOI:  https://doi.org/10.1016/j.bbrc.2025.151419
Front Pharmacol. 2025 ;16 1510372

Zinc regulates microglial polarization and inflammation through IKBα after spinal cord injury and promotes neuronal repair and motor function recovery in mice.

Daoyong Li, Mingyu Bai, Zhanpeng Guo, Yang Cui, Xifan Mei, He Tian, Zhaoliang Shen.

   Introduction: Spinal cord injury (SCI) leads to severe inflammation and neuronal damage, resulting in permanent loss of motor and sensory functions. Zinc ions have shown potential in modulating inflammation and cellular survival, making them a promising therapeutic approach for SCI. This study investigates the mechanisms of zinc ion treatment in SCI, focusing on its effects on inflammation.
Methods: We used transcriptomic analysis to identify key pathways and genes involved in the inflammatory response in a mouse model of SCI. In vitro studies assessed the impact of zinc ions on inflammation, cell polarization, and apoptosis. IKBα expression was evaluated as a potential target of zinc ions, both in cultured cells and in vivo.
Results: Transcriptomic analysis revealed that zinc ions modulate inflammatory pathways through IKBα, which inhibits NF-κB activity. In vitro, zinc treatment upregulated IKBα expression, reducing inflammation, polarization, and apoptosis. These results were confirmed in the SCI mouse model, where zinc ions also reduced inflammation and cell death.
Discussion: Our findings highlight a novel mechanism by which zinc ions regulate inflammation in SCI by upregulating IKBα and inhibiting NF-κB activation. This suggests potential therapeutic applications of zinc ions in SCI and other inflammatory conditions, warranting further investigation into their clinical benefits.

Keywords:  functional recovery; inflammatory response; microglial polarization; spinal cord injury; zinc

DOI:  https://doi.org/10.3389/fphar.2025.1510372
Acta Neuropathol Commun. 2025 Feb 13. 13(1): 30

The tumour microenvironment of pilocytic astrocytoma evolves over time via enrichment for microglia.

Thomas J Stone, Jessica C Pickles, Olumide Ogunbiyi, Shireena A Yasin, Catherine A Taylor, Saira W Ahmed, Jane Chalker, Carryl Dryden, Iwona Slodkowska, Emily Pang, Mark Kristiansen, Rachel Williams, Helena Tutill, Charlotte A Williams, Gaganjit K Madhan, Leysa Forrest, Tony Brooks, Mike Hubank, Debbie Hughes, Paula Proszek, Grzegorz Pietka, Erin Peat, Darren Hargrave, Thomas S Jacques.

  Pilocytic astrocytoma (PA) is the commonest low-grade tumour affecting children and is frequently experienced as a chronic disease associated with extended treatment, periods of regrowth, and long-term disability. This contrasts with the view of PA as a benign tumour with positive clinical outcomes and raises the fundamental question of biologically driven change over time within these tumours, which will impact diagnosis, stratification, and management. To investigate the molecular, cellular, and pathological stability of PA we performed RNA sequencing, methylation array profiling, immunohistochemistry, and targeted panel DNA sequencing on a cohort of 15 PA patients with matched primary/longitudinal samples at a mean sampling interval of 2.7 years. Through pairwise analysis of primary versus longitudinal tumour samples we identified changes to immune-related pathways within the expression and methylation profiles of longitudinal PA. Further interrogation of these changes revealed an enrichment over time for microglial cell populations, which was validated by immunohistochemistry against common monocyte/microglial markers. Moreover, immunohistochemical characterisation revealed concurrent increases in the expression of M2-like and anti-inflammatory markers. Microglial enrichments were consistent across the cohort and were not adequately explained by a range of potential confounders, including receipt of adjuvant therapy. Taken together, these data challenge the idea of pilocytic astrocytoma as a static entity and indicate that they consistently accumulate microglia over time, potentially co-opting the immune microenvironment towards an anti-inflammatory phenotype that may affect the natural course and treatment response of the tumours.

Keywords:  Immune microenvironment; Low-grade glioma; Microglia; Pilocytic astrocytoma

DOI:  https://doi.org/10.1186/s40478-024-01922-9
Behav Brain Res. 2025 Feb 10. pii: S0166-4328(25)00066-X. [Epub ahead of print] 115480

Experimenters' sex modulates anxiety-like behavior, contextual fear, and microglial oxytocin transcription in mice.

Mai Sakai, Zhiqian Yu, Rosanne Picotin, Tomoko Kasahara, Yoshie Kikuchi, Chiaki Ono, Mizuki Hino, Yasuto Kunii, Yuko Maejima, Kenju Shimomura, Miharu Nakanishi, Takaaki Abe, Hatsumi Yoshii, Hiroaki Tomita.

  Oxytocin (OXT) is a neuropeptide known for modulating anxiety and fear memory. We have reported that microglial cytokine regulates contextual fear memory and that microglial OXT positively correlates with cytokine secretion. However, the relationship between contextual fear memory and microglial OXT expression remains unclear. We evaluated whether experimental handling minimizes anxiety-like behaviors through microglial OXT expression and its effects on contextual fear response in a sex-dependent manner. Male and female mice were cup-handled for seven days by male or female experimenters (four groups: male mice with or without handling and female mice with or without handling). Post-handling anxiety-like behavior was assessed using elevated plus maze (EPM) and light-dark box (LDB) tests. Microglial Oxt transcription was evaluated using real-time PCR following handling and footshock. Our results showed that handling by female experimenters induced anxiolytic behaviors in the EPM and LDB and microglial Oxt transcripts in male mice but did not show a direct causal relationship. After handling by male experimenters, male mice exhibited stronger conditional freezing responses than female mice. In contrast, female mice exhibited significantly weaker freezing, independent of Oxt transcription in the microglia and the paraventricular hypothalamic nucleus. These findings suggest that handling influences anxiety and microglial Oxt expression, while conditional freezing reflects a sex-dependent effect by experimenter sex.

Keywords:  Anxiety-like behavior; Contextual fear memory; Handling; Oxytocin; Sex differences

DOI:  https://doi.org/10.1016/j.bbr.2025.115480
Neurol Res Int. 2025 ;2025 8948290

Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation.

Shao Qin Tiong, Raxshanaa N Mohgan, Jia Yee Quek, Jennifer Yue Suan Liew, Grace Yee Seen Wong, Zi Qing Thang, Zhi Ling Chan, Sook Yee Gan, Elaine Wan Ling Chan.

  Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.

Keywords:  Alzheimer's disease; Aβ-induced neurotoxicity and microglia-mediated neuroinflammation; TGF-β signaling

DOI:  https://doi.org/10.1155/nri/8948290
J Inflamm (Lond). 2025 Feb 11. 22(1): 6

Alpha-1 antitrypsin reduces inflammation and vasculopathy in mice with oxygen-induced retinopathy.

Varaporn Suphapimol, Yu-Han Liu, Sandro Prato, Alexander Karnowski, Charles Hardy, Adriana Baz Morelli, Abhirup Jayasimhan, Devy Deliyanti, Jennifer L Wilkinson-Berka.

   BACKGROUND: Damage to the retinal vasculature is a major cause of vision loss and is influenced by a pro-inflammatory environment within retinal tissue. Alpha-1 antitrypsin (AAT) is a potent inhibitor of serine proteases and has anti-inflammatory properties. We hypothesised that AAT could reduce inflammation and vasculopathy in neovascular retinopathies including oxygen-induced retinopathy (OIR).
METHODS: Litters of C57BL/6J mice were randomised to develop OIR by exposure to high oxygen between postnatal days 7 to 12 resulting in vaso-obliteration (phase I OIR), and then room air from postnatal days 12 to 18 resulting in neovascularisation (phase II OIR). Control mice were exposed to room air. Separate cohorts of mice were administered control vehicle or human AAT (120 mg/kg) by intraperitoneal injection every second day in phase I or phase II OIR.
RESULTS: In phase I OIR, plasma levels of AAT were reduced compared to room air controls, and AAT treatment reduced vaso-obliteration. In phase II OIR, AAT treatment influenced inflammation by reducing the density of ionised calcium binding adaptor protein 1 + cells (microglia/macrophages) and modulating their cell process length and reducing mRNA levels of tumour necrosis factor and monocyte chemoattractant protein-1, but not interleukin-1b and interleukin-6 in retina. Furthermore, AAT treatment reduced retinal neovascularisation, gliosis, vascular endothelial growth factor mRNA and protein expression, and vascular leakage, compared to OIR controls.
CONCLUSIONS: This research demonstrates the vasculo-protective actions of AAT, and thereby the potential of AAT as a therapeutic option for neovascular retinopathies.

Keywords:  Alpha-1 antitrypsin; Inflammation; Microglia; Neovascularisation; Oxygen-induced retinopathy; Vascular leakage

DOI:  https://doi.org/10.1186/s12950-025-00431-3
Apoptosis. 2025 Feb 09.

Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage.

Guijun Wang, Zhijie Li, Wenrui Han, Qi Tian, Chengli Liu, Shengming Jiang, Xi Xiang, Xincan Zhao, Lei Wang, Jianming Liao, Mingchang Li.

  Subarachnoid hemorrhage (SAH), representing 5-10% of all stroke cases, is a cerebrovascular event associated with a high mortality rate and a challenging prognosis. The role of IRG1-regulated itaconate in bridging metabolism, inflammation, oxidative stress, and immune response is pivotal; however, its implications in the early brain injury following SAH remain elusive. The SAH nerve inflammation model was constructed by Hemin solution and BV2 cells. In vitro and in vivo SAH models were established by intravascular puncture and Hemin solution treatment of HT22 cells. To explore the relationship between IRG1 and neuroinflammation by interfering the expression of Irg1 in BV2 cells. By adding itaconate and its derivatives to explore the relationship between mitophagy and ferroptosis. IRG1 knockdown increased the expression of inflammatory factors and induced the transformation of microglia to pro-inflammatory phenotype after SAH; Itaconate and itaconate derivative 4-OI can reduce oxidative stress and lipid peroxidation level in neuron after SAH, and reduce EBI after SAH; IRG1/ itaconate promotes mitophagy through PINK1/Parkin signaling pathway to inhibit neuronal ferroptosis. IRG1 can improve nerve inflammation after SAH, M2 of microglia induced polarization. IRG1/ Itaconate participates in mitophagy through PINK1/Parkin to alleviate neuronal ferroptosis after SAH and play a neuroprotective role.

Keywords:  Ferroptosis; IRG1; Itaconate; Mitophagy; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1007/s10495-025-02077-1
Front Psychiatry. 2024 ;15 1495598

Pituitary adenylyl cyclase-activating polypeptide modulates the stress response: the involvement of different brain areas and microglia.

Anika Singh, Paul Shim, Sadaf Naeem, Shafiqur Rahman, Kabirullah Lutfy.

  Stress is necessary for survival. However, chronic unnecessary stress exposure leads to cardiovascular, gastrointestinal and neuropsychiatric disorders. Thus, understanding the mechanisms involved in the initiation and maintenance of the stress response is essential since it may reveal the underpinning pathophysiology of these disorders and may aid in the development of medication to treat stress-mediated diseases. Pituitary adenylyl cyclase activating polypeptide (PACAP) and its receptors (PAC1, VPAC1 and VPAC2) are expressed in the hypothalamus and other brain areas as well as in the adrenal gland. Previous research has shown that this peptide/receptor system serves as a modulator of the stress response. In addition to modulating the stress response, this system may also be connected to its emerging role as neuroprotective against hypoxia, ischemia, and neurodegeneration. This article aims to review the literature regarding the role of PACAP and its receptors in the stress response, the involvement of different brain regions and microglia in PACAP-mediated modulation of the stress response, and the long-term adaptation to stress recognizable clinically as survival with resilience while manifested in anxiety, depression and other neurobehavioral disorders.

Keywords:  BNST; PACAP; amygdala; hypothalamus; microglia; pituitary, adrenal gland; stress

DOI:  https://doi.org/10.3389/fpsyt.2024.1495598
J Neuroimmune Pharmacol. 2025 Feb 14. 20(1): 21

Pharmacological Depletion of Microglia Protects Against Alcohol-Induced Corticolimbic Neurodegeneration During Intoxication in Male Rats.

Erika R Carlson, Jennifer K Melbourne, Kimberly Nixon.

  Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causal role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia > 90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.

Keywords:  Alcohol use disorder; Ethanol; Hippocampus; Microglia; Neurodegeneration

DOI:  https://doi.org/10.1007/s11481-025-10173-x
Front Immunol. 2025 ;16 1538920

Assessing in-vitro models for microglial development and fetal programming: a critical review.

Steven Schepanski, Gonza B Ngoumou, Claudia Buss, Georg Seifert.

  This review evaluates in-vitro models for studying how maternal influences during pregnancy impact the development of offspring microglia, the immune cells of the central nervous system. The models examined include primary microglia cultures, microglia cell lines, iPSC-derived microglia, PBMC-induced microglia-like cells, 3D brain organoids derived from iPSCs, and Hofbauer cells. Each model is assessed for its ability to replicate the in-vivo environment of the developing brain, with a focus on their strengths, limitations, and practical challenges. Key factors such as scalability, genetic and epigenetic fidelity, and physiological relevance are highlighted. Microglia cell lines are highly scalable but lack genetic and epigenetic fidelity. iPSC-derived microglia provide moderate physiological relevance and patient-specific genetic insights but face operational and epigenetic challenges inherent to reprogramming. 3D brain organoids, derived from iPSCs, offer an advanced platform for studying complex neurodevelopmental processes but require extensive resources and technical expertise. Hofbauer cells, which are fetal macrophages located in the placenta and share a common developmental origin with microglia, are uniquely exposed to prenatal maternal factors and, depending on fetal barrier maturation, exhibit variable epigenetic fidelity. This makes them particularly useful for exploring the impact of maternal influences on fetal programming of microglial development. The review concludes that no single model comprehensively captures all aspects of maternal influences on microglial development, but it offers guidance on selecting the most appropriate model based on specific research objectives and experimental constraints.

Keywords:  brain development; developmental origin of health and diseases; fetal programming; in-vitro models; microglia; neurodevelopmental disorders; neuroimmunology and microglia; neuropsychiatry

DOI:  https://doi.org/10.3389/fimmu.2025.1538920
Adv Exp Med Biol. 2025 ;1468 139-142

Understanding the Different Microglia Functional States to Modulate Their Activity in Retinal Degeneration.

Raela B Ridley, Yixiao Wang, Cristhian J Ildefonso.

  Recent advances in genomic, transcriptomic, and imaging have advanced our understanding of microglia cells and their role in neurodegenerative diseases. These dynamic cells can change into distinct functional subpopulations with unique genetic markers and specialized functions once they migrate to the injury site. The model illustrated in Fig. 23.1 predicts that once the tissue recovers from the injury, the predominant microglia functional state should be the homeostatic state and localize within the retina's inner plexiform layers. However, microglia cells do not return to the predominantly homeostatic functional state during retinal degeneration (von Bernhardi et al., Front Aging Neurosci 7:124, 2015). Studies in animal models suggest that during retinal degeneration, rather than maintaining the homeostatic state, microglia can become dysregulated and remain pro-inflammatory, thus exacerbating tissue damage (Rashid et al., Front Immunol 10:1975, 2019; Wang and Cepko, Front Immunol 13:843558, 2022). To address the increased inflammation and excessive phagocytosis seen in these models, some studies employed the use of genetic and pharmacological methods to deplete retinal microglia (Zhao et al., EMBO Mol Med 7:1179-1197, 2015; Wang et al., J Neurosci 36:2827-2842, 2016). Because of their multiple physiological functions, microglia depletion is not a feasible therapeutic approach to address neuroinflammation. Instead, manipulating microglia functions should take center stage when developing therapies for neuroinflammation. Thus, defining the genetic network that regulates microglia functional states is essential to developing therapies to modulate microglia.

Keywords:  Anti-inflammatory; Functional states; Homeostatic; Immunology; Inflammation; Microglia; Neuroprotection; Proliferative; Retinal degeneration

DOI:  https://doi.org/10.1007/978-3-031-76550-6_23
Adv Exp Med Biol. 2025 ;1468 143-147

Progress in Assessing Retinal Microglia Using Single-Cell RNA Sequencing.

Sarah J Karlen, Kaitryn E Ronning, Marie E Burns.

  Retinal degeneration is the leading cause of both inherited and age-related vision loss, and often leads to neuroimmune activation and a heterogeneous population of microglia and monocyte-derived macrophages. A common method to study the innate immune response during retinal degeneration is single-cell RNA sequencing, but the best way to obtain and analyze these cells over the course of degeneration remains debated. Here, we compare two common methods of retinal cell preparation (collagenase digestion with immune cell enrichment by FACS; Col/FACS vs papain digestion of the whole retina without enrichment; Pap/Whole) and three different algorithms for database integration (CCA, RPCA, and Harmony) to examine microglia in healthy retinas. We find that the Pap/Whole dissociation produced a smaller fraction of activated microglial cells and that the Harmony integration of microglia isolated by these two methods resulted in the highest Silhouette score, indicating the greatest separation of microglia subclusters from these data sets.

Keywords:  Dataset integration; Microglia; Neuroinflammation; Retinal dissociation; Transcriptome; scRNAseq

DOI:  https://doi.org/10.1007/978-3-031-76550-6_24