bims-microg 2025-08-03 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–08–03
twenty-six papers selected by
Marcus Karlstetter, Universität zu Köln

TREM2-Mediated Myeloid Cells Protect Against Pathological Choroidal Neovascularization.
Colony Stimulating Factor-1 (CSF-1) and Interleukin-34 (IL-34) Differentially Alter White Matter and Gray Matter Microglia and Oligodendrocyte Progenitor Cells.
G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.
Dual-targeting CSF1R signaling attenuates neurotoxic myeloid activation and preserves photoreceptors in retinitis pigmentosa.
Treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization via activating mitophagy post-TBI.
25-hydroxysterol mitigates microgravity-induced retinal damage by suppressing microglial inflammation through disrupting lipid raft formation.
Dihydroartemisinin enhances remyelination by switching microglia to the reparative phenotype.
Interleukin-4 induces CD11c+ microglia leading to amelioration of neuropathic pain in mice.
Non-mutated human tau stimulates Alzheimer's disease-relevant neurodegeneration in a microglia-dependent manner.
AD16 Modulates Microglial Activation and Polarization to Mitigate Neuroinflammation in Ischemic Stroke Models Through α7nAChR-ERK-STAT3 Signaling.
Involvement of Microglia in Retinal Ganglion Cell Injury Induced by IOP Elevation in a Rat Ex Vivo Acute Glaucoma Model.
Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model.
Functional Diversity of Two Novel Embryonic Microglial Subpopulations and Their Developmental Trajectories in Developing Mouse Brains.
Microglia depletion in a mouse model of prenatal and postnatal immune activation.
Aggrecan protects against plaque accumulation and is essential for proper microglial responses to plaques.
Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease.
Reconstructing Alzheimer's disease one cell type at a time using in vitro tricultures.
Activation of the non-canonical Wnt5a signaling pathway following optic nerve injury induces time-dependent changes in pro- and anti-inflammatory gene expression.
Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.
Gut-derived bacterial vesicles carrying lipopolysaccharide promote microglia-mediated synaptic pruning.
Uncovering plaque-glia niches in human Alzheimer's disease brains using spatial transcriptomics.
Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis.
HIV Protein TAT Dysregulates Multiple Pathways in Human iPSCs-Derived Microglia.
Ursolic acid ameliorates cerebral ischemia-reperfusion injury by inhibiting NF-κB/NLRP3-mediated microglia pyroptosis and neuroinflammation.
STAT1 and STAT6 orchestrate Cbs transcription and transsulfur metabolism in microglia and contribute to parkinson's disease-related neuroinflammation.
Translocator protein facilitates neutrophil-mediated mucosal inflammation in inflammatory bowel diseases.

FASEB J. 2025 Jul 31. 39(14): e70881

TREM2-Mediated Myeloid Cells Protect Against Pathological Choroidal Neovascularization.

Tianxi Wang, Manon Szczepan, Austin T Gregg, Xingyan Wang, Lois E H Smith, Ye Sun.

  Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration, a leading cause of irreversible vision loss in the elderly. While immune dysregulation and myeloid cell activation have been implicated in CNV pathogenesis, the molecular mechanisms by which myeloid subsets influence NV remain incompletely understood. Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor enriched in microglia and tissue macrophages, known to play protective roles in retinal and neurodegenerative diseases. However, its function in CNV has not been fully characterized. In this study, we investigated the role of TREM2 in CNV using transcriptomic, genetic, and functional approaches. Single-cell RNA sequencing revealed selective upregulation of Trem2 in activated microglia and macrophages following laser-induced CNV. These findings were validated at the protein level using immunostaining, which confirmed robust TREM2 expression in lesion-associated IBA1+ myeloid cells. Functionally, Trem2 haploinsufficiency exacerbated CNV lesion size and vascular leakage, indicating a protective role in disease modulation. Transcriptomic profiling demonstrated that Trem2-expressing myeloid cells exhibit distinct angiogenic and inflammasome-related gene signatures, suggesting that TREM2 regulates angiogenesis through modulation of inflammatory pathways. We further examined the functional interaction between TREM2 and suppressor of cytokine signaling 3 (SOCS3), another anti-inflammatory mediator upregulated during CNV. Using compound mutant mice, we showed that Trem2 and SOCS3 function through overlapping but independent anti-angiogenic programs, and their combined deficiency leads to additive worsening of CNV pathology. These findings establish TREM2 as a key regulator of myeloid cell function and angiogenesis in the diseased retina.

Keywords:  SOCS3; Trem2; choroidal neovascularization; macrophages; microglia; myeloid cells

DOI:  https://doi.org/10.1096/fj.202501793R
J Neurochem. 2025 Aug;169(8): e70186

Colony Stimulating Factor-1 (CSF-1) and Interleukin-34 (IL-34) Differentially Alter White Matter and Gray Matter Microglia and Oligodendrocyte Progenitor Cells.

Audrée S Rumberger, Lauryn A Vassel, Caroline C Hess, Annabel S Barnett, Brady J Johnson, Sayed Hassan, Jonathan P Godbout, Anzela Niraula.

  Colony stimulating factor-1 receptor (CSF-1R) signaling is necessary for microglia development and maintenance throughout life. The CSF-1R ligands, CSF-1 and interleukin-34 (IL-34), are indispensable for microglia survival in white matter and gray matter, respectively. While CSF-1 has been studied to a greater extent, the role of IL-34 in microglia function and in the brain overall is much less understood. Here, we examined the region-specific effects of intracerebroventricular (i.c.v.) CSF-1 and IL-34 administration on microglia and oligodendrocyte lineage cells in mice at two timepoints. At 3 days post-intervention, IL-34 increased microglial CD68 levels and the microglia population in the hippocampal CA1 region, whereas CSF-1 increased the microglia population in the corpus callosum. Furthermore, CSF-1, but not IL-34, reduced the oligodendrocyte progenitor cell population in the corpus callosum. These effects were no longer observed at 7 days, revealing the transient nature of the microglial response. Together, these findings demonstrate that in addition to relying on specific signals for survival, microglia respond differently to CSF-1R ligands in a brain microenvironment-dependent manner. These findings highlight the need to better understand microglia in the context of their location, which could provide key insights into the pathogenesis of neuroimmune disorders that predominantly affect gray matter or white matter areas.

Keywords:  colony stimulating factor‐1; colony stimulating factor‐1 receptor; interleukin‐34; microglia; oligodendrocyte progenitor cells; white matter

DOI:  https://doi.org/10.1111/jnc.70186
Neuron. 2025 Jul 23. pii: S0896-6273(25)00478-7. [Epub ahead of print]

G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.

Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao.

  Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.

Keywords:  ADGRG1; Alzheimer’s disease; G-protein-coupled receptor; MYC; microglia; neurodegeneration; phagocytosis; β-amyloid

DOI:  https://doi.org/10.1016/j.neuron.2025.06.020
J Neuroinflammation. 2025 Jul 26. 22(1): 193

Dual-targeting CSF1R signaling attenuates neurotoxic myeloid activation and preserves photoreceptors in retinitis pigmentosa.

Jiangmei Wu, Jing Zhang, Bin Lin.

  Retinitis pigmentosa (RP), a group of inherited retinal diseases characterized by progressive photoreceptor degeneration, features prominent microglial activation and monocyte-derived macrophage infiltration. While colony-stimulating factor 1 receptor (CSF1R) shows diverse roles in regulating microglial survival and behaviors in various neurodegenerative diseases, its functional significance in RP pathogenesis remains unclear. In this study, we observed upregulated CSF1R signaling specifically within disease-associated myeloid cells in the rd10 mouse model of RP. Targeted intervention via intravitreal CSF1R neutralizing antibodies and systemic PLX5622 administration achieved reduced myeloid proliferation and pro-inflammatory cytokine production and greater photoreceptor survival. Notably, CSF1R potentiation using recombinant IL-34 or CSF1 exacerbated neuroinflammation and accelerated photoreceptor degeneration. Mechanistic investigations revealed that infiltrating monocyte depletion by clodronate liposomes significantly reduced macrophage infiltration and preserved visual function. Using CX3CR1CreER/+/R26iDTR/+/rd10 mouse model, we observed that diphtheria toxin-mediated microglia ablation preserved retinal function. Overall, our findings demonstrate the prominent role of CSF1R in neurotoxic myeloid activation in the context of RP. Our results provide preclinical proof-of-concept that dual targeting of retinal and peripheral CSF1R pathways may offer a mutation-agnostic therapeutic strategy for inherited retinal degenerations.

Keywords:  CSF1R; Macrophages; Microglia; Neuroinflammation; Photoreceptor degeneration; Proliferation

DOI:  https://doi.org/10.1186/s12974-025-03525-0
Free Radic Biol Med. 2025 Jul 24. pii: S0891-5849(25)00849-4. [Epub ahead of print]239 155-176

Treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization via activating mitophagy post-TBI.

Jie Chen, Tong Zhu, Xixi Yang, Zhuojin Yang, Mengqing Shen, Boyuan Gu, Danmei Wang, Yuxiang Zhang, Mingxia Zhang, Siyu Sun, Jun Yu, Chunxia Yan.

  Moderate-intensity treadmill exercise has emerged as a promising therapeutic intervention for traumatic brain injury (TBI), yet its precise mechanisms remain unclear. Emerging evidence suggests that STING-mediated microglial pyroptosis and polarization might exacerbate TBI-induced pathological damage. Our previous work demonstrated treadmill exercise's inhibitory effects on the STING level, and mitophagy has been recognized as a crucial regulator of STING activity. Therefore, we aimed to test the possibility that treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization partially through activating mitophagy post-TBI. First, we found that TBI-induced pyroptosis primarily occurred in neurons and microglia, along with pro-inflammatory M1 microglial polarization in the injured cortex. Remarkably, treadmill exercise could effectively reverse those pathological changes, demonstrating its anti-pyroptotic and anti-inflammatory potential. Then, we explored the dynamic expression of STING post-TBI, and found a progressively increased trend of STING in neurons, astrocytes, and microglia from 6 h to 35 days after TBI, with the most prominent rise in microglia. Notably, STING knockdown markedly diminished TBI-induced pyroptosis and prompted a shift in microglial polarization from M1 to M2. Furthermore, STING overexpression could partly abolish the treadmill exercise's neuroprotective effects against pyroptosis and inflammation post-TBI, suggesting that the anti-pyroptosis and anti-inflammatory effects of treadmill exercise were partly established via inhibiting the STING pathway. Crucially, pharmacological inhibition of mitophagy using mdivi-1 could partly reverse the treadmill exercise's suppressive effects on STING signaling, establishing mitophagy as the likely regulatory mechanism through which treadmill exercise regulates the STING pathway. To conclude, these findings demonstrated that treadmill exercise ameliorates STING-mediated microglial pyroptosis and M1 polarization, at least partially through enhancing mitophagy following TBI.

Keywords:  Microglia polarization; Mitophagy; Pyroptosis; Stimulator of interferon genes; Traumatic brain injury; Treadmill exercise

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.034
NPJ Microgravity. 2025 Aug 01. 11(1): 49

25-hydroxysterol mitigates microgravity-induced retinal damage by suppressing microglial inflammation through disrupting lipid raft formation.

Jee Hoon Lee, Dae Yu Kim.

Spaceflight-associated neuro-ocular syndrome (SANS) poses a significant risk to astronaut vision during long-duration missions, yet its immunological underpinnings remain poorly defined. Here, we identify retinal microglia as key mediators of ocular degeneration under simulated microgravity (SMG). Using a 3D clinostat model, we show that SMG induces early activation of retinal pigment epithelium (RPE), which in turn promotes microglial activation and triggers a feedforward cascade of RPE damage and neuronal loss. We further demonstrate that 25-hydroxycholesterol (25-HC), an oxysterol capable of penetrating the blood-retinal barrier, attenuates this inflammatory cascade by disrupting lipid raft formation in microglia. Low-dose 25-HC suppresses the recruitment of cytokine receptors to lipid rafts, mitigating microglia-driven retinal injury. These findings uncover a critical immunopathological axis underlying SANS and propose 25-HC as a non-invasive, immunomodulatory countermeasure to preserve retinal integrity during spaceflight.

DOI: https://doi.org/10.1038/s41526-025-00507-7
J Neuroinflammation. 2025 Aug 01. 22(1): 197

Dihydroartemisinin enhances remyelination by switching microglia to the reparative phenotype.

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.

   BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: By highlighting the importance of microglia in promoting myelin regeneration, our study proved DHA as a promising candidate for promoting remyelination.

Keywords:  Cholesterol recycling; Demyelinating diseases; Dihydroartemisinin; Microglia; Remyelination

DOI:  https://doi.org/10.1186/s12974-025-03510-7
Elife. 2025 Aug 01. pii: RP105087. [Epub ahead of print]14

Interleukin-4 induces CD11c+ microglia leading to amelioration of neuropathic pain in mice.

Keita Kohno, Ryoji Shirasaka, Keita Hirose, Takahiro Masuda, Makoto Tsuda.

  Neuropathic pain, a debilitating chronic pain condition, is a major clinical challenge. The pleiotropic cytokine interleukin-4 (IL-4) has been shown to suppress neuropathic pain in rodent models, but its underlying mechanism remains unclear. Here, we show that intrathecal administration of IL-4 to mice with spinal nerve transection (SpNT) increased the number of CD11c+ microglia (a microglia subset important for pain remission) in the spinal dorsal horn (SDH) and that this effect of IL-4 was essential for its ameliorating effect on SpNT-induced pain hypersensitivity. Furthermore, in mice with spared nerve injury (SNI), another model in which pain remission does not occur, the emergence of CD11c+ SDH microglia was curtailed, but intrathecal IL-4 increased their emergence and ameliorated pain hypersensitivity in a CD11c+ microglia-dependent manner. Our study reveals a mechanism by which intrathecal IL-4 ameliorates pain hypersensitivity after nerve injury and provides evidence that IL-4 increases CD11c+ microglia with a function that ameliorates neuropathic pain.

Keywords:  interleukin4; microglia; mouse; neuropathic pain; neuroscience; spinal cord

DOI:  https://doi.org/10.7554/eLife.105087
Sci Rep. 2025 Jul 29. 15(1): 27664

Non-mutated human tau stimulates Alzheimer's disease-relevant neurodegeneration in a microglia-dependent manner.

Ethan R Roy, Qiang Wang, Kexin Huang, Sanming Li, Yuanyuan Fan, Estrella Escobar, Constance L Atkins, Shuning Huang, Juan J Herrera, Wenbo Li, Clare Pridans, Xiaobo Zhou, Cynthia Ju, Wei Cao.

  The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimer's disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the mouse brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by cellular stress in neurons and reactive gliosis in multiple brain regions. Notably, the lifelong absence of microglia significantly and differentially influenced the extent of neurodegeneration in the hippocampus and thalamus. Therefore, our study established an AD-relevant tauopathy mouse model, elucidated both neuron-intrinsic and neuron-extrinsic responses, and highlighted critical and complex roles of microglia in modulating tau-driven neurodegeneration.

Keywords:  Alzheimer; Microglia; Neurodegeneration; Neuroinflammation; Tau; Tauopathy

DOI:  https://doi.org/10.1038/s41598-025-12869-9
CNS Neurosci Ther. 2025 Jul;31(7): e70519

AD16 Modulates Microglial Activation and Polarization to Mitigate Neuroinflammation in Ischemic Stroke Models Through α7nAChR-ERK-STAT3 Signaling.

Guo-Jian Zhao, Li-Mei Zhang, Si-Rou Wang, Mei Yang, Jia-Hao Jiang, Bo-Xiang Yuan, Cheng Huang, Zhi-Hua Huang, Xiao-Lu Tang, Tao Chen.

   BACKGROUND: Neuroinflammation constitutes a critical pathological event subsequent to ischemic stroke. AD16, a novel anti-neuroinflammatory compound, has demonstrated efficacy in alleviating neuroinflammation in neonatal rats induced by ischemia-hypoxia. This study aims to elucidate the therapeutic utility and underlying mechanisms of AD16 in an adult ischemic stroke rat model.
METHODS: A rat transient middle cerebral artery occlusion (tMCAO) model was employed. Neurological function was evaluated using the Longa and Garcia JH scores, motor function was assessed through rotary rod and CatWalk gait analysis, and brain injury was examined via TTC and Nissl staining. Molecular docking techniques simulate the binding of a target compound to a potential target. Western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to detect microglia phenotype, pro-inflammatory factors, and activation of signaling molecules.
RESULTS: AD16 treatment improved neural function in tMCAO rats, reduced cerebral infarction volume and brain water content, preserved blood-brain barrier integrity, and inhibited pro-inflammatory cytokines. Molecular docking showed AD16 has high affinity for α7nAChR, TLR4, ERK, and STAT3. AD16 increased α7nAChR, CD206, and p-ERK protein levels, while decreasing CD40, CD68, TLR4, and p-STAT3. These effects were reversed by α-BTX (α7nAChR inhibitor) and U0126 (ERK inhibitor).
CONCLUSION: AD16 may inhibit microglia activation and polarization via the α7nAChR-ERK-STAT3 pathway, thus reducing neuroinflammation from cerebral ischemia and protecting the brain. This study suggests AD16 as a potential treatment for ischemic stroke.

Keywords:  AD16; ischemic stroke; microglia polarization; neuroinflammation; α7nAChR‐ERK‐STAT3

DOI:  https://doi.org/10.1111/cns.70519
Biomedicines. 2025 Jul 08. pii: 1670. [Epub ahead of print]13(7):

Involvement of Microglia in Retinal Ganglion Cell Injury Induced by IOP Elevation in a Rat Ex Vivo Acute Glaucoma Model.

Taimu Sato, Makoto Ishikawa, Yukitoshi Izumi, Naoya Shibata, Kota Sato, Michiko Ohno-Oishi, Hiroshi Tawarayama, Hiroshi Kunikata, Charles F Zorumski, Toru Nakazawa.

  Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4-NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4-NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes.

Keywords:  NLRP3 inflammasome; PLX5622; glaucoma; interleukin-1β; intraocular pressure; neuroinflammation; neuroprotection

DOI:  https://doi.org/10.3390/biomedicines13071670
Brain Behav Immun. 2025 Jul 26. pii: S0889-1591(25)00290-9. [Epub ahead of print]129 874-889

Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model.

Hami Hemati, Madison B Blanton, Heather E True, Jude Koura, Rupak Khadka, Kathleen A Grant, Ilhem Messaoudi.

  Alcohol-induced dysregulation of microglial activity is associated with neuroinflammation, cognitive decline, heightened risk for neurodegenerative diseases, alcohol dependence, and escalation of alcohol drinking. Given the challenge of longitudinally sampling primary microglia, we optimized an in vitro method to differentiate peripheral blood mononuclear cells (PBMC) from rhesus macaque (RM) into induced microglia-like cells (RM-iMGLs). The RM-iMGLs displayed transcriptional profiles distinct from monocyte progenitors and closely resembling primary microglia. Notably, morphological features showed that differentiated RM-iMGLs derived from subjects with chronic alcohol consumption (CAC), while bigger, exhibited a bipolar-like morphology. Additionally, dysregulation in key inflammatory and regulatory markers, along with increased baseline phagocytic activity, was observed in CAC-derived RM-iMGLs. Phenotypic and functional assessments following LPS stimulation indicated the enrichment of a CD86+ hyper-inflammatory subpopulation in RM-iMGLs derived from ethanol-consuming animals, accompanied by an overall increase in immune reactivity, indicative of a heightened inflammatory state. Collectively, these findings demonstrate that in vitro differentiation of PBMCs offers a minimally invasive yet highly translational approach to studying the impact of CAC on microglial function and that CAC reshapes both functional and transcriptional profiles of RM-iMGLs, which require further investigation at the single-cell level.

Keywords:  Chronic alcohol consumption; Induced-microglia; Microglia; Transcriptome

DOI:  https://doi.org/10.1016/j.bbi.2025.07.022
Glia. 2025 Jul 25.

Functional Diversity of Two Novel Embryonic Microglial Subpopulations and Their Developmental Trajectories in Developing Mouse Brains.

Siao Muk Cheng, Chi-Lin Ho, Shiou-Lan Chen, Yi-Te Huang, Pin-Cheng Mao, Tzu-Chia Lin, Jia-Shing Chen, H Sunny Sun, Daw-Yang Hwang, Chun-Hsien Chu.

  As the primary brain-resident macrophages, embryonic microglia (EM) display functional diversity and significant heterogeneity, which are essential for normal brain development and growth. However, the heterogeneous nature of EM and their developmental trajectory remain contentious. This study isolated individual cells from the brains of embryonic day 14 (E14) mice without using a microglial cell sorting method and subsequently performed single-cell RNA sequencing (scRNA-seq) analysis. Unsupervised subclustering of the microglial population based on gene expression profiles revealed two novel EM subclusters: approximately 60% EM1 (CD68-negative and Iba-1-positive) and about 40% EM2 (CD68- and Iba-1-double-positive). Additionally, bioinformatics analyses indicated that the EM1 cluster represents relatively early and immature microglia with high proliferative capacity. In contrast, the EM2 cluster exhibits a higher expression of genes involved in the stepwise program of microglial development, synaptic phagocytosis, regulation of neuron differentiation and projection, and interaction with other brain cells. To further confirm these findings, double or triple immunofluorescence staining of Iba-1, CD68, or the presynaptic marker synaptophysin demonstrated the presence of the EM1 and EM2 clusters in E14 mouse brains, as well as increased synaptic phagocytosis in the EM2 cluster. Moreover, by monitoring their proportional changes in the brains on postnatal days 1, 14, and 90, our data disclosed the developmental trajectory of the EMs as they transition from CD68-negative to CD68-positive after the postnatal period stages. Overall, this study opens new avenues for exploring the functional diversity and developmental trajectory of EMs during embryonic brain development and growth.

Keywords:  CD68; embryonic microglia; heterogeneity; phagocytosis

DOI:  https://doi.org/10.1002/glia.70064
Brain Behav Immun. 2025 Jul 29. pii: S0889-1591(25)00287-9. [Epub ahead of print]129 935-947

Microglia depletion in a mouse model of prenatal and postnatal immune activation.

Naomi Ciano Albanese, Ignacio Del Castillo, Giulia Ragaglia, Giulia Castellano, Maria Antonietta Ajmone-Cat, Roberta De Simone, Marilena Griguoli, Laura Ricceri.

  Risk for neurodevelopmental disorders can be related to early immune stimulations and altered brain microglial functions. Here we investigated the behavioural and electrophysiological effects of microglia depletion in a mouse model of developmental immune activation. C57BL/6J pregnant mice were exposed on gestational day 12.5 to polyinosinic:polycytidylic acid (Poly I:C), subsequently, on postnatal day 9, offspring was further treated with lipopolysaccharide (LPS). At weaning, offspring was exposed throughout adolescence (4 weeks) to either a diet containing Colony Stimulating Factor-1 receptor inhibitor (PLX5622, PLX) to reduce microglia, or standard diet. Hence, we assessed i) explorative and anxiety-like responses, social responsiveness and cognitive abilities between 7th and 8th postnatal week; ii) synaptic transmission and neuroinflammatory and microglial molecular markers in the medial prefrontal cortex (mPFC) and hippocampus (HP) at the end of treatment (8th postnatal week). EIA condition reduced locomotor activity and impaired discrimination between a familiar and a novel social stimulus (social novelty response) only in male mice. Also, PLX treatment selectively affected the same social novelty response in males (both saline and EIA) and in EIA females, intriguingly sparing saline females. Unexpectedly, EIA condition per se did not affect spontaneous excitatory and inhibitory synaptic transmission in both mPFC and HP, whereas EIA combined with PLX reduced inhibitory transmission in males (both mPFC and HP) and neuron excitability in both male and female mPFC. Interestingly, PLX had per se sex- and region- specific effects increasing inhibitory transmission in female mPFC and decreasing excitatory transmission in male HP. Molecular data, beside a robust downregulation of microglia markers in PLX diet groups, also showed that EIA condition increased interleukin-6 (il-6) expression in EIA males in both mPFC and HP, and elevated il-1β levels in both sexes in mPFC and in male HP. Overall, these findings indicate that males have an increased vulnerability to the long-term behavioural and inflammatory effects of the EIA condition, and are more likely to exhibit behavioural and electrophysiological changes in response to microglia depletion.

Keywords:  Autism spectrum disorders; Microglia depletion; Perinatal inflammation; Sex differences; Social novelty

DOI:  https://doi.org/10.1016/j.bbi.2025.07.018
Cell Rep. 2025 Jul 30. pii: S2211-1247(25)00835-6. [Epub ahead of print]44(8): 116064

Aggrecan protects against plaque accumulation and is essential for proper microglial responses to plaques.

Rocio A Barahona, Nellie E Kwang, Aashna R Kono-Soosaipillai, Giovanna Rubio Salgado, Kristine M Tran, Yueh-Hao Lu, Siddharth Reddy, Celia da Cunha, Eric Velazquez-Rivera, Joshua D Crapser, Xiangmin Xu, Lindsay A Hohsfield, Kim N Green.

  Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent evidence implicates extracellular matrix (ECM) dysfunction in disease pathogenesis, including extensive loss of perineuronal nets (PNNs). PNNs are neuron-ensheathing condensed ECM structures composed of chondroitin sulfate proteoglycans, including the main constituent aggrecan (ACAN). To explore the role of PNNs in AD, we utilize the 5xFAD model and genetically target Acan in Nestin-expressing cells, resulting in loss of ACAN and ablation of the PNN structure. In 5xFAD mice, ACAN cKO results in increased plaque deposition, reduced plaque sphericity, and impaired microglia-plaque association. Single-cell spatial transcriptomics identifies an enhanced disease-associated microglia (DAM) phenotype in 5xFAD ACAN cKO mice, which is accompanied by decreased dystrophic neurite formation. Collectively, our data suggest that PNNs may play a crucial role in mediating the microglial response to plaques.

Keywords:  5xFAD; Alzheimer’s disease; CP: Cell biology; CP: Neuroscience; aggrecan; amyloid-beta; extracellular matrix; microglia; neurodegeneration; perineuronal nets; plaques

DOI:  https://doi.org/10.1016/j.celrep.2025.116064
Sci Transl Med. 2025 Jul 30. 17(809): eadx0027

Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease.

Ricardo D'Oliveira Albanus, Gina M Finan, Logan Brase, Nicholas Sweeney, Tae Yeon Kim, Shuo Chen, Yeonsu Ryoo, Joseph Park, Qi Guo, Abhirami Kannan, Mariana Acquarone, Shih-Feng You, Brenna C Novotny, Emily M Mace, Patricia M Ribeiro Pereira, John C Morris, David M Holtzman, Eric McDade, Martin Farlow, Jasmeer P Chhatwal, Bruno A Benitez, Laura Piccio, Richard J Perrin, Greg T Sutherland, Qin Ma, Celeste M Karch, Doo Yeon Kim, Rudolph E Tanzi, Hongjun Fu, Oscar Harari, Tae-Wan Kim.

Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer's disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged TREM2 knockout human induced pluripotent stem cell-derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.

DOI: https://doi.org/10.1126/scitranslmed.adx0027
Trends Neurosci. 2025 Jul 29. pii: S0166-2236(25)00152-3. [Epub ahead of print]

Reconstructing Alzheimer's disease one cell type at a time using in vitro tricultures.

Tatiana A Giovannucci, Charles Arber, Selina Wray.

  In a recent study, Lish and colleagues used a fully human-based, induced pluripotent stem cell (iPSC)-derived triculture model of neurons, astrocytes, and microglia to delineate non-cell autonomous contributions to familial Alzheimer's disease (AD). This approach offers a versatile platform to explore early disease mechanisms, dissect cell-cell interactions, and support the development of targeted therapeutic or biomarker strategies.

Keywords:  astrocytes; glia; iPSC; microglia; neurodegeneration; neurons

DOI:  https://doi.org/10.1016/j.tins.2025.07.010
Growth Factors. 2025 Jul 31. 1-12

Activation of the non-canonical Wnt5a signaling pathway following optic nerve injury induces time-dependent changes in pro- and anti-inflammatory gene expression.

Alexander W Venanzi, Gabrielle A Albano, Paola E Parrales, Abigail S Hackam.

  Optic nerve (ON) injury leads to retinal ganglion cell (RGC) degeneration and axonal atrophy. Wnt ligands are embryonic growth factors that regulate cellular differentiation and survival. We recently demonstrated that canonical and non-canonical Wnt signaling induces RGC survival and axonal regrowth after optic nerve crush (ONC) injury in mouse. Here, we investigated whether the non-canonical Wnt5a ligand induces pro-regenerative inflammation after ONC. Mice were intravitreally injected with Wnt5a or saline during ONC and retina tissue was collected for QPCR and immunofluorescence. We demonstrated that expression of arginase 1, a marker of anti-inflammatory microglia, was upregulated by Wnt5a in injured retinas, whereas iNOS, a marker of neurotoxic microglia, was suppressed. Wnt5a also induced time-dependent changes in pro-inflammatory genes Gal3, TNFα, P2RY12 and IL-6 and the anti-inflammatory gene IL-27. These results indicate that Wnt5a is an immunomodulatory ligand in the retina after ONC injury.

Keywords:  Inflammation; Wnt5a; arginase 1 (Arg1); non-canonical Wnt signaling; optic nerve crush; optic nerve regeneration

DOI:  https://doi.org/10.1080/08977194.2025.2539128
Alzheimers Dement. 2025 Aug;21(8): e70502

Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.

Marta Fernández-Matarrubia, Andrea Valera-Barrero, Mónica Renuncio-García, Marcos Aguilella, Carmen Lage, Sara López-García, J Gonzalo Ocejo-Vinyals, Francisco Martínez-Dubarbie, Guglielmo Di Molfetta, Ana Pozueta-Cantudo, María García-Martínez, Andrea Corrales-Pardo, María Bravo, Marcos López-Hoyos, Juan Irure-Ventura, Kaj Blennow, Nicholas J Ashton, Henrik Zetterberg, Pascual Sánchez-Juan, Eloy Rodríguez-Rodríguez.

   INTRODUCTION: The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear.
METHODS: We assessed changes in microglial and astrocytic biomarkers in a well-characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events.
RESULTS: Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau-181 (p-tau181) and neurogranin, and correlated with CSF S100 calcium-binding protein beta (S100β). CSF chitinase-3-like protein 1 (YKL-40) mediated the association between CSF p-tau181 and total tau (t-tau), whereas CSF S100β and neurofilament light showed mutual influence.
DISCUSSION: Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL-40 and S100β contribute to the progression of downstream neurodegenerative changes.
HIGHLIGHTS: Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau-181. Chitinase-3-like protein 1 (YKL-40) mediated tau-induced neurodegeneration. S100 calcium-binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

Keywords:  S‐100 calcium‐binding protein beta (S100β); astrocyte; biomarkers; chitinase‐3‐like protein 1 (YKL‐40); glial fibrillary acidic protein (GFAP); microglia; preclinical Alzheimer´s disease; soluble triggering receptor expressed on myeloid cells 2 (sTREM2); structural equation modeling

DOI:  https://doi.org/10.1002/alz.70502
Alzheimers Dement. 2025 Aug;21(8): e70331

Gut-derived bacterial vesicles carrying lipopolysaccharide promote microglia-mediated synaptic pruning.

Xiaoduo Zhao, Jiayi Yu, Bin Xu, Zhi Xu, Xia Lei, Shilong Han, Shangfei Luo, Can Zhang, Guoping Peng, Jing Li, Jie Yu, Yi Ling, Zhongqin Fan, Wei Mo, Ying Yang, Jing Zhang.

   INTRODUCTION: Growing evidence links gut microbiota (GM) to Alzheimer's disease (AD). Elevated lipopolysaccharide (LPS) levels, a Gram-negative bacteria component, are found in AD brains, but how LPS breaches the blood-brain barrier (BBB) remains unclear. Hypotheses suggest that bacteria-derived extracellular vesicles (bEVs) may transport LPS across the BBB.
METHODS: bEVs were extracted from human and mouse feces and blood, and LPS levels were measured. In vivo imaging and immunofluorescence confirmed the transport of blood LPS-carrying bEVs across the BBB. The role of these bEVs in microglia was investigated both in vivo and in vitro.
RESULTS: Elevated LPS-containing bEVs were detected in the plasma of AD patients compared to healthy individuals. These bEVs activated microglial Piezo1, consequently precipitating an excessive synaptic pruning process mediated by the C1q-C3 complement pathway.
DISCUSSION: These findings illuminate the complex interplay between the gut microbiota, bEVs, neuroinflammation, and synaptic plasticity - a key early event in AD - offering insights for potential therapeutic interventions.
HIGHLIGHTS: GM-derived bEVs can traverse the BBB. LPS was necessary for bEVs' penetration into the brain, and bEVs might be closely related to AD progression. bEVs mediated microglial activation and synaptic pruning via C1q-C3 complement pathway. Microglia Piezo1 was involved in bEV-induced excessive synaptic pruning.

Keywords:  Alzheimer's disease; C1q; Piezo1; bacteria‐derived extracellular vesicles; lipopolysaccharide; synaptic splicing

DOI:  https://doi.org/10.1002/alz.70331
Mol Neurodegener Adv. 2025 ;1(1): 2

Uncovering plaque-glia niches in human Alzheimer's disease brains using spatial transcriptomics.

Denis R Avey, Bernard Ng, Ricardo A Vialle, Nicola A Kearns, Katia de Paiva Lopes, Artemis Iatrou, Sashini De Tissera, Himanshu Vyas, Devin M Saunders, Daniel J Flood, Jishu Xu, Shinya Tasaki, Chris Gaiteri, David A Bennett, Yanling Wang.

   Background: Amyloid-beta (Aβ) plaques and their associated glial responses are hallmark features of Alzheimer's disease (AD), yet their interactions within the human brain remain poorly defined.
Methods: We applied spatial transcriptomics (ST) and immunohistochemistry (IHC) to 78 postmortem brain sections from 21 individuals in the Religious Orders Study and Memory and Aging Project (ROSMAP). We paired ST with histological data and stratified spots into major categories of plaque-glia niches based on Aβ, GFAP, and IBA1 intensity. Leveraging published ROSMAP single-nucleus RNA-seq data, we examined differences in gene expression, cellular composition, and intercellular communication across these niches. Neuronal and glial changes were validated by IHC and quantitative analyses. We further characterized glial responses using gene set enrichment analysis (GSEA) with known mouse glial signatures and human AD-associated microglial states. Finally, we used iPSC-derived multicellular cultures and single-cell RNA sequencing (scRNA-seq) to identify cell types that, upon short-term Aβ exposure, recapitulate the glial responses observed in the human spatial data.
Results: Low-Aβ regions, enriched for diffuse plaques, exhibited transcriptomic profiles consistent with greater neuronal loss than high-Aβ regions. High-glia regions showed increased expression of inflammatory and neurodegenerative pathways. Spatial glial responses aligned with established gene modules, including plaque-induced genes (PIGs), oligodendrocyte (OLIG) responses, disease-associated microglia (DAM), disease-associated astrocytes (DAA), and human AD-associated microglial states, indicating that diverse glial phenotypes emerge around plaques and shape the local immune environment. IHC confirmed elevated neuronal apoptosis near low-Aβ plaques and greater CD68 abundance and synaptic loss near glia-high plaques. In vitro, iPSC-derived microglia-but not astrocytes-exposed to Aβ displayed transcriptomic changes that closely mirrored the glial states identified in our ST dataset.
Conclusions: Our study provides a comprehensive spatial transcriptomic dataset from human AD brain tissue and bridges spatial gene expression with traditional neuropathology. By integrating ST, snRNA-seq, and human multicellular models, we map cellular states and molecular events within plaque-glia niches. This work offers a spatially resolved framework for dissecting plaque-glia interactions and reveals new insights into the cellular and molecular heterogeneity underlying neurodegenerative pathology.
Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-025-00002-z.

Keywords:  Alzheimer’s Disease; Amyloid-beta; Glia; Human Brain; Spatial Transcriptomics

DOI:  https://doi.org/10.1186/s44477-025-00002-z
Brain Behav Immun. 2025 Jul 23. pii: S0889-1591(25)00286-7. [Epub ahead of print]129 839-856

Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis.

Zoë A MacDowell Kaswan, Alexandra K Brooks, Myrna Hurtado, Emily Y Chen, Andrew J Steelman, Robert H McCusker.

  Viral encephalitis is a serious condition that causes acute neuroinflammation, neurodegeneration, cognitive deficits and behavioral changes, while putting patients at risk of developing seizures (ictogenesis) and post-encephalitis epilepsy. Intracerebral injection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) is a model of viral encephalitis that causes behavioral seizures along with substantial neurodegeneration and neuroinflammation. This model is considered a benchmark preclinical paradigm for the investigation of hippocampal-dependent viral ictogenesis and temporal lobe epilepsy. Inflammation-induced indolealine2,3-deoxygenase (Ido) 1 and 2 initiate the conversion of tryptophan into kynurenine, which is subsequently converted into downstream neuroactive metabolites with the ability to modify behavioral seizures. Ido1 and Ido2 have also been shown to have non-redundant roles in modulating several inflammatory diseases. We have previously shown that Ido1 deficiency increases TMEV-induced behavioral seizure incidence using wild type (WT, C57BL/6J) mice. Here, we extend those findings to Ido2 deficiencies. We find that Ido2KO (knockout) mice have equivalent TMEV-induced behavioral seizure incidence and hippocampal gene expression relative to wild type WT mice. However, while TMEV infection causes an increase in Iba1+ staining throughout the hippocampus (indicating microglial activation) this effect is ameliorated in Ido2KO mice. Microglia, the resident innate immune cells of the brain, are critical for TMEV clearance but may also contribute to ictogenesis. Therefore, based on Ido2-dependent differences in microglia activation, we examined TMEV-induced ictogenesis in mice with microglial-specific Ido1 and Ido2 deficiencies. We found that microglial Ido2, but not Ido1, deficiency reduced ictogenesis but caused minimal changes in hippocampal gene expression. In vitro treatments revealed that microglia respond to TMEV infection via inflammatory signals rather than directly to viral infection itself. In sum, we demonstrate that Ido2 plays a key role in microglial response to TMEV and that, when the effects of Ido2 deficiency are limited to microglia, Ido2 deficiency is protective against ictogenesis.

Keywords:  Encephalitis; Epilepsy; Ictogenesis; Ido1; Ido2; Indoleamine 2,3-dioxygenase; Inflammation; Microglia; Seizures; TMEV; Viral infection

DOI:  https://doi.org/10.1016/j.bbi.2025.07.017
Life (Basel). 2025 Jul 09. pii: 1082. [Epub ahead of print]15(7):

HIV Protein TAT Dysregulates Multiple Pathways in Human iPSCs-Derived Microglia.

Liam Liyang Guo, Robert Jiang, Yan Cheng, Brooke Russell, Sanders Y Yan, Ming-Lei Guo.

  In the era of combined antiretroviral therapy, around 50% of chronic HIV (+) individuals show varying degrees of memory and cognitive deficiency (NeuroHIV), a phenomenon of accelerated brain aging. HIV protein transactivator of transcription (TAT) has been well-accepted as a risk factor contributing to NeuroHIV through dysregulating microglia (Mg) functions. Previous studies have demonstrated that HIV-TAT can affect lipid metabolism, immune responses, autophagy, and senescence in rodent Mg. However, due to the significant species differences between rodent and human Mg (hMg), it is essential to take caution when interpreting the results obtained from rodent models into human conditions. For the unanswered questions, we generated hMg from human inducible pluripotent stem cells (iPSCs) and exposed them to HIV-TAT. The results obtained from Flow analysis and immunostaining experiments reveal that TAT can induce LD accumulation and increase perilipin-2 (Plin2) levels in hMg. Meanwhile, HIV-TAT can upregulate autophagosome formation and p53 levels. Through human immune array assay, we showed that TAT can increase the expression of multiple pro-inflammatory mediators, cytokines, and chemokines in hMg. Extensive bioinformatic analysis shows that HIV-TAT can affect multiple neuroimmune signaling pathways and indicates that microRNAs (miRNAs) are coherently involved in such dysregulation. Overall, our findings provide direct evidence showing that HIV-TAT can affect lipid metabolism, autophagy, senescence signaling, and multiple neuroimmune-related pathways in hMg and indicate the roles of novel miRNAs on NeuroHIV pathogenesis, which deserves further investigations.

Keywords:  NeuroHIV; human inducible pluripotent stem cells; lipid droplet accumulation microglia; microRNAs; transactivator of transcription

DOI:  https://doi.org/10.3390/life15071082
Front Pharmacol. 2025 ;16 1622131

Ursolic acid ameliorates cerebral ischemia-reperfusion injury by inhibiting NF-κB/NLRP3-mediated microglia pyroptosis and neuroinflammation.

Junbin Liu, Xiaoting Zhang, Jingpei Guo, Yun Zhang, Jinming Fan, Junfeng Liu, Jiawen Chen, Jiawei Jiang, Benshuai Yu, Ke Zhang, Bin Zhou.

   Introduction: Neuroinflammation is a pivotal factor in the pathophysiology process of ischemic stroke. Undue inflammatory responses are the main cause of neuronal death and infarct enlargement after reperfusion, but there is currently no effective clinical treatment method. Pyroptosis plays an important role in post-stroke neuroinflammation. Inhibiting pyroptosis may be a potential method for treating ischemic stroke. Ursolic acid (UA) is a natural antioxidant with an antipyroptotic effect, but the mechanism of UA in cerebral ischemia-reperfusion injury remains unknown.
Methods: We evaluated UA's neuroprotective effects in a transient middle cerebral artery occlusion (tMCAO) mouse model via oral administration. TTC staining was carried out to measure infarct volume. Neuronal damage was assessed through TUNEL and FJC staining. Open field test and novel object recognition test were conducted to evaluate anxiety-like behavior and hippocampal-related memory. Double-immunofluorescence was conducted to detect pyroptotic microglia. In vitro, BV-2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were treated with UA. Cell viability was measured utilizing CCK-8 assay. RT-qPCR was used to measure NLRP3, IL-1β, and IL-18 mRNA levels. ELISA was utilized to measure IL-1β and IL-18 concentration. PMA was used as an agonist in rescue experiment. Immunostaining was used to observe nuclear/cytoplasmic distribution of NF-κB. Western blot was used to evaluate the protein expression of pyroptosis markers.
Results: UA significantly reduced infarct volume, alleviated neuronal damage, and improved cognitive and functional recovery in tMCAO mice. Additionally, UA downregulated the density of NLRP3, Caspase-1, and GSDMD positive microglia and the production of IL-1β and IL-18 in the ischemic penumbra of tMCAO mice. These effects were replicated in OGD/R-challenged BV-2 cells. Mechanistically, UA suppressed NF-κB activation, and PMA treatment reversed its therapeutic benefits in both models.
Discussion: Our findings demonstrate that UA attenuates microglial pyroptosis by inhibiting NF-κB signaling, thereby reducing neuroinflammation and ischemic brain injury. This study highlights UA's potential as a therapeutic agent for ischemic stroke.

Keywords:  cerebral ischemia-reperfusion injury; microglia; neuroinflammation; pyroptosis; ursolic acid

DOI:  https://doi.org/10.3389/fphar.2025.1622131
Cell Mol Life Sci. 2025 Jul 30. 82(1): 294

STAT1 and STAT6 orchestrate Cbs transcription and transsulfur metabolism in microglia and contribute to parkinson's disease-related neuroinflammation.

Yang Liu, Zhen Wang, Ya-Ting Ma, Yu-Xuan Chen, Xin-Yi Qian, Xiao-Ou Hou, Bo Wan, Hai-Gang Ren, Li-Fang Hu.



Keywords:  CBS; DJ-1; Microglia; STAT1; STAT6; Transsulfur metabolism

DOI:  https://doi.org/10.1007/s00018-025-05768-9
World J Gastroenterol. 2025 Jul 21. 31(27): 109239

Translocator protein facilitates neutrophil-mediated mucosal inflammation in inflammatory bowel diseases.

Qiong He, Xiao-Han Wu, Dong-Lang Jiang, Ri-Tian Lin, Fang Xie, Yi-Hui Guan, Ai-Hua Fei.

   BACKGROUND: Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic gastrointestinal disorders with an increasing global prevalence and significant healthcare impact. The exact etiology of this condition remains unclear. Neutrophils play a critical role in IBD pathogenesis. Translocator protein (TSPO), a mitochondrial protein linked to immune responses, has demonstrated potential as an inflammatory marker. However, its role in IBD remains underexplored.
AIM: To investigate the role of TSPO in IBD pathogenesis, particularly in neutrophils.
METHODS: Bioinformatics analyses of Gene Expression Omnibus datasets (GE75214, GSE94648, GSE156776) assessed TSPO expression in IBD patients. TSPO expression was evaluated in human IBD samples, neutrophiles and a chronic colitis mouse model. Neutrophil function was examined in 18 samples using reactive oxygen species (ROS) production and neutrophil extracellular trap (NET) formation assays. Positron emission tomography-computed tomography (PET-CT) imaging and histology from 12 mice revealed TSPO expression in colitis. PET-CT and immunofluorescence staining assessed TSPO expression in brain under neuroinflammation condition.
RESULTS: Bioinformatics analysis revealed elevated TSPO expression in the intestinal mucosa and peripheral blood of patients with IBD, especially in neutrophils. This was confirmed by quantitative real-time polymerase chain reaction and immunohistochemical staining, which showed a significant upregulation of TSPO in active IBD. Neutrophils from patients with UC and CD exhibited higher TSPO expression, which correlated with increased ROS production and NET formation. In a mouse model of dextran sodium sulfate-induced chronic colitis, TSPO was upregulated in the colonic neutrophils and brain tissues, indicating its systemic involvement. PET-CT imaging showed enhanced TSPO uptake in the inflamed colon and brain regions, particularly in the microglia, highlighting neuroinflammation.
CONCLUSION: TSPO is significantly upregulated in neutrophils in IBD and contributes to intestinal inflammation. Its elevated expression in gut highlights its potential as a promising therapeutic target for IBD.

Keywords:  Crohn's disease; Expression; Gut-brain axis; Inflammatory bowel disease; Intestinal inflammation; Neuroinflammation; Neutrophil; Positron emission tomography-computed tomography; Translocator protein; Ulcerative colitis

DOI:  https://doi.org/10.3748/wjg.v31.i27.109239