bims-microg 2025-05-04 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–05–04
sixteen papers selected by
Marcus Karlstetter, Universität zu Köln

TIM-3 regulates microglial function.
Microglia in the periphery.
Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.
Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1+ microglia.
Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders.
Biomimetic elasticity compressed assembly controls rapid intracerebral drug release to reverse microglial dysfunction.
Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection.
Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa.
A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.
Diffuse traumatic brain injury induced stimulator of interferons (STING) signaling in microglia drives cortical neuroinflammation, neuronal dysfunction, and impaired cognition.
Targeting microglial NAAA-regulated PEA signaling counters inflammatory damage and symptom progression of post-stroke anxiety.
Microglia aging in the hippocampus advances through intermediate states that drive activation and cognitive decline.
The P2X7R-antagonist AFC-5128 ameliorates chronic experimental autoimmune encephalomyelitis in a preventive and therapeutic paradigm.
Astrocyte-derived complement C3 facilitated microglial phagocytosis of synapses in Staphylococcus aureus-associated neurocognitive deficits.
Chronic IL-21 drives neuroinflammation and promotes lipid accumulation in microglia.
Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques.

Nat Rev Drug Discov. 2025 May 02.

TIM-3 regulates microglial function.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00078-y
Nat Rev Immunol. 2025 Apr 28.

Microglia in the periphery.

Lucy Bird.

DOI: https://doi.org/10.1038/s41577-025-01180-3
Immunity. 2025 Apr 21. pii: S1074-7613(25)00138-4. [Epub ahead of print]

Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.

William H Aisenberg, Carleigh A O'Brien, Madison Sangster, Fazeela Yaqoob, Yuanchao Zhang, Brian Temsamrit, Searlait Thom, Luca Gosse, Sai Chaluvadi, Bilal Elfayomi, Gavin Lee, Vidhur Polam, Eli M Levitt, Gary Liu, Sonia I Lombroso, Kelsey M Nemec, Gavin Clowry, Cassaundra Nieves, Priyanka Rawat, Emily Church, Daniel Martinez, Clarissa Shoffler, Daliya Kancheva, Christopher Petucci, Deanne Taylor, Julia Kofler, Daniel Erskine, Kiavash Movahedi, Mariko L Bennett, F Chris Bennett.

  Krabbe disease, also named globoid cell (GC) leukodystrophy (GLD) for its distinct lipid-laden macrophages, is a severe leukodystrophy caused by galactosylceramidase (GALC) mutations. Hematopoietic stem cell transplant (HSCT) ameliorates disease and is associated with central nervous system (CNS) engraftment of GALC+ donor macrophages. Yet, the role of macrophages in GLD pathophysiology and HSCT remains unclear. Using single-cell sequencing, we revealed early interferon response signatures that preceded progressively severe macrophage dyshomeostasis and identified a molecular signature of GCs, which we validated in human brain specimens. Genetic depletion and direct microglia replacement by CNS monocyte injection rapidly replaced >80% of endogenous microglia with healthy macrophages in the twitcher (GalcW355∗) mouse model of GLD. Perinatal microglia replacement completely normalized transcriptional signatures, rescued histopathology, and doubled average survival. Overall, we uncovered distinct forms of microglial dysfunction and evidence that direct, CNS-limited microglia replacement improves a monogenic neurodegenerative disease, identifying a promising therapeutic target.

Keywords:  Krabbe disease; disease-associated macrophage; globoid cell; globoid cell leukodystrophy; hematopoietic stem cell transplant; microglia; microglia replacement

DOI:  https://doi.org/10.1016/j.immuni.2025.03.019
Immunity. 2025 Apr 24. pii: S1074-7613(25)00169-4. [Epub ahead of print]

Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1+ microglia.

Jonathan Bastos, Carleigh O'Brien, Mónica Vara-Pérez, Myrthe Mampay, Lynn van Olst, Liam Barry-Carroll, Daliya Kancheva, Sophia Leduc, Ayla Line Lievens, Leen Ali, Vladislav Vlasov, Laura Meysman, Hadis Shakeri, Ria Roelandt, Hannah Van Hove, Karen De Vlaminck, Isabelle Scheyltjens, Fazeela Yaqoob, Sonia I Lombroso, Maria Breugelmans, Gilles Faron, Diego Gomez-Nicola, David Gate, F Chris Bennett, Kiavash Movahedi.

  Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the distinct identity of embryonically derived BAMs and microglia. Using xenotransplantation, we found that human monocytes exhibited similar behavior, enabling identification of putative Mo-Microglia in Alzheimer's disease individuals. In mice and humans, monocyte ontogeny shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bona fide microglial identity. Our results illuminate brain macrophage development and highlight monocytes as an abundant progenitor source for brain macrophage replacement therapies.

Keywords:  border-associated macrophage; brain immunology; hematopoietic stem cell transplantation; microglia; microglia replacement; monocyte; neurodegeneration; ontogeny

DOI:  https://doi.org/10.1016/j.immuni.2025.04.006
Sci Transl Med. 2025 Apr 30. 17(796): eads6111

Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders.

Dadian Chen, Chen Wang, Xi Chen, Jiayu Li, Shuai Chen, Yanzhong Li, Fangling Ma, Tingting Li, Mengling Zou, Xin Li, Xiaohua Huang, Yun-Wu Zhang, Yingjun Zhao, Guojun Bu, Honghua Zheng, Xiao-Fen Chen, Jie Zhang, Li Zhong.

Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover, BM-derived cells that migrate to the brain do not recapitulate the phenotypic and functional properties of resident microglia. Here, we present a microglia transplantation strategy devoid of any conditioning, termed "tricyclic microglial depletion for transplantation" (TCMDT). This approach leverages three cycles of microglial depletion using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, creating an optimal window for efficient engraftment of exogenous microglia. Transplantation of primary cultured microglia by TCMDT successfully restored the identity and functions of endogenous microglia. To evaluate the therapeutic potential of TCMDT, we applied this strategy to two distinct mouse models of neurologic disorder. In a Sandhoff disease model, a neurodegenerative lysosomal storage disorder caused by hexosaminidase subunit beta (Hexb) deficiency, TCMDT effectively replaced deficient microglia, attenuating neurodegeneration and improving motor performance. Similarly, in an Alzheimer's disease (AD)-related amyloid mouse model carrying the triggering receptor expressed on myeloid cells 2 (Trem2) R47H mutation, our transplantation strategy rescued microglial dysfunction and mitigated AD-related pathology. Overall, our study introduces TCMDT as a practical, efficient, and safe approach for microglia replacement, suggesting therapeutic potential for treating neurological disorders associated with microglial dysfunction.

DOI: https://doi.org/10.1126/scitranslmed.ads6111
Sci Adv. 2025 May 02. 11(18): eadr0656

Biomimetic elasticity compressed assembly controls rapid intracerebral drug release to reverse microglial dysfunction.

Guochen Han, Yi Jin, Kaiwen Bai, Qiaofei Du, Xiaochen Gu, Ling Tao, Jianping Zhou, Huaqing Zhang, Yang Ding.

The regulation of microglial dysfunction has become increasingly prominent in treatment of Alzheimer's disease (AD). Herein, we develop a scalable polymer-involved biomimetic assembly that responds to intracerebral reactive oxygen species (ROS) for elastic spreading and concentration-dependent drug therapy. Structurally, a polymer of thermally sensitive deformation is selected for hydrophobic loading of curcumin (Cur) and coordinative grafting onto ultrasmall ceria (CeO2) by elastic compression at transition temperature, which is further sealed by self-polymerized dopamine with apolipoprotein decoration to improve intracerebral shuttling. When triggered by ROS in the lesions, burst exposure of Cur and polymer-linked CeO2 (PCeO2) is achieved. The concentrated Cur switches amyloid-β (Aβ)-activated microglia into normal for mobilizing phagocytosis, and CeO2 has sustainable antioxidant capacity to prevent microglial mitochondrial damage after phagocytosis of PCeO2-captured Aβ. After administration, our findings reveal microglia-mediated Aβ clearance, neuroprotection, and ROS elimination in AD mice. Collectively, this biomimetic assembly provides a promising approach in AD treatments.

DOI: https://doi.org/10.1126/sciadv.adr0656
Theranostics. 2025 ;15(11): 4890-4908

Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection.

Soo-Jin Oh, Young Yeon Kim, Ruiying Ma, Seok Tae Choi, Se Myeong Choi, Jong Hyun Cho, Ji-Yeun Hur, Yongjin Yoo, Kihoon Han, Hosun Park, Jeanho Yun, Ok Sarah Shin.

  Rationale: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of dysfunctional mitochondria. Herpes simplex virus type 1 (HSV1) may be a risk factor for the neuropathology linked to amyloid β (Aβ) accumulation. However, the mechanisms underlying HSV1-associated mitochondrial dysfunction in AD remain unclear. ALT001 is a novel drug that ameliorates AD-related cognitive impairment via ULK1/Rab9-mediated alternative mitophagy. In this study, we investigated the effects of ALT001 on the neurodegeneration-related microglial signatures associated with HSV1 infection. Methods: Molecular mechanisms and physiological functions of mitophagy was investigated in HSV1-infected microglia, including primary murine and human embryonic stem cell (ESC)-derived microglia (ES-MG), as well as in a microglia-neuron co-culture system. Microglial gene signatures following HSV1 infection in the presence or absence of ALT001 were analyzed using bulk RNA sequencing, and the effects of ALT001 on microglial phagocytosis and microglia-mediated immune responses were further evaluated by flow cytometry and cytokine profiles. Results: HSV1 infection inhibited PINK1/Parkin-mediated mitophagy via HSV1-encoded protein kinase US3, resulting in mitochondrial dysfunction in both human and mouse microglia. Furthermore, transcriptomic analysis of HSV1-infected microglia revealed an upregulation of distinct microglial genes associated with disease-associated microglia (DAM)-like phenotype and pro-inflammatory activity. Pharmacological targeting of mitophagy using ALT001 prevents mitochondrial damage caused by HSV1 through ULK1/Rab9-mediated pathway. Furthermore, ALT001-induced ULK1/Rab9-dependent mitophagy restricts HSV1 infection by activating interferon-mediated antiviral immunity. Consequently, ALT001 reduces HSV1-triggered neuroinflammation, recovers HSV1-altered microglial phagocytosis for Aβ, and efficiently reverses morphological and molecular abnormalities in HSV1-infected microglia by triggering mitophagy in ES-MG. ALT001 also suppressed HSV1-mediated Aβ accumulation and neurodegeneration in the microglia-neuron co-culture and cerebral organoid model. Conclusions: In this study, we identified a critical molecular link between HSV1 and AD-related microglial dysfunction. Furthermore, our findings provide an evidence that therapeutic targeting of alternative mitophagy via ALT001 effectively interfere with HSV1-induced microglial dysfunction and alleviate neurodegeneration.

Keywords:  ALT001; Microglia; alternative mitophagy; herpes simplex virus 1 (HSV1); neurodegeneration

DOI:  https://doi.org/10.7150/thno.105953
Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2423134122

Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa.

Jing Zhang, Wei Yang, Jiangmei Wu, Bin Lin.

  Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by the progressive loss of photoreceptors. Neuroinflammation has been implicated in the pathophysiology of RP and its progression. Previous studies have suggested that the transforming growth factor-beta-activated kinase 1 (TAK1) plays a pivotal role in regulating acute and chronic neuroinflammation. However, the functional role of TAK1 in neuroinflammation remains unclear in RP. Here, we observed TAK1 upregulation in activated microglia of the rd10 mouse model of RP. To create the conditional deletion of TAK1 in microglia, we backcrossed Cx3cr1CreER/CreER mice and Tak1fl/fl mice onto rd10 background. We found that both heterozygous (rd10;Cx3cr1CreER/+;Tak1fl/+) and homozygous (rd10;Cx3cr1CreER/+;Tak1fl/fl) deletion of microglial TAK1 slowed down photoreceptor degeneration but with distinct mechanisms. The heterozygous TAK1 deficiency resulted in a reduction in the activation and proliferation of microglia and the release of proinflammatory cytokines by inhibiting STAT3 signaling. In contrast, the homozygous TAK1 deficiency induced apoptosis in microglia via the TNF/RIPK1/CASP3 signaling pathway, contributing to the reduction of microglia-mediated neurotoxicity and subsequent preservation of photoreceptors in RP. Overall, our findings highlight the crucial role of TAK1 in the survival and activation of microglia. We propose that targeting microglial TAK1, considering its expression levels and subsequent signal transduction, could offer a promising personalized therapeutic strategy for individuals with RP regardless of underlying genetic causes.

Keywords:  RIPK1; STAT3; TAK1; microglia; photoreceptor degeneration

DOI:  https://doi.org/10.1073/pnas.2423134122
Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2427073122

A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.

Liyang Zhang, Jingxuan Yang, Zhijun Zhou, Yu Ren, Bo Chen, Anliu Tang, Kailiang Zhang, Chuntao Li, Hongshu Zhou, Kar-Ming Fung, Chao Xu, Chunsheng Kang, James D Battiste, Michael S Bronze, Courtney W Houchen, Zhixiong Liu, Ian F Dunn, Webster K Cavenee, Min Li.

  Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt- And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor-microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.

Keywords:  TREM1; exosome; glioblastoma; microglia

DOI:  https://doi.org/10.1073/pnas.2427073122
J Neuroinflammation. 2025 Apr 30. 22(1): 128

Diffuse traumatic brain injury induced stimulator of interferons (STING) signaling in microglia drives cortical neuroinflammation, neuronal dysfunction, and impaired cognition.

Jonathan M Packer, Samantha G Giammo, Lynde M Wangler, Amara C Davis, Chelsea E Bray, Jonathan P Godbout.

  Neuropsychiatric complications including depression and cognitive impairment develop, persist, and worsen in the years after traumatic brain injury (TBI), negatively affecting life and lifespan. Inflammatory responses mediated by microglia are associated with the transition from acute to chronic neuroinflammation after TBI. Moreover, type I interferon (IFN-I) signaling is a key mediator of inflammation during this transition. Thus, the purpose of this study was to determine the degree to which a microglia-specific knockout of the stimulator of interferons (STING) influenced TBI-induced neuroinflammation, neuronal dysfunction, and cognitive impairment. Here, microglial inducible STING knockout (CX₃CR1Cre/ERT2 x STINGfl/fl) mice were created and validated (mSTING-/-). Diffuse brain injury (midline fluid percussion) in male and female mice increased STING expression in microglia, promoted microglial morphological restructuring, and induced robust cortical inflammation and pathology 7 days post injury (dpi). These TBI-associated responses were attenuated in mSTING-/- mice. Increased cortical astrogliosis and rod-shaped microglia induced by TBI were independent of mSTING-/-. 7 dpi, TBI induced 237 differentially expressed genes (DEG) in the cortex of functionally wildtype (STINGfl/fl) associated with STING, NF-κB, and Interferon Alpha signaling and 85% were attenuated by mSTING-/-. Components of neuronal injury including reduced NeuN expression, increased cortical lipofuscin, and increased neurofilament light chain in plasma were increased by TBI and dependent on mSTING. TBI-associated cognitive tasks (novel object recognition/location, NOR/NOL) at 7 dpi were dependent on mSTING. Notably, the TBI-induced cognitive deficits in NOR/NOL and increased cortical inflammation 7 dpi were unaffected in global interferon-α/β receptor 1 knockout (IFNAR1) mice. In the final study, the RNA profile of neurons after TBI in STINGfl/fl and mSTING-/- mice was assessed 7 dpi by single nucleus RNA-sequencing. There was a TBI-dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and oxytocin signaling and increases in cilium assembly and PTEN signaling. Overall, mSTING-/- prevented 50% of TBI-induced DEGs in cortical neurons. Collectively, ablation of STING in microglia attenuates TBI-induced interferon responses, cortical inflammation, neuronal dysfunction, neuronal pathology, and cognitive impairment.

Keywords:  And Type I Interferons ; Cognitive Dysfunction; Inflammation; Microglia; Stimulator of Interferon Genes; TBI

DOI:  https://doi.org/10.1186/s12974-025-03451-1
Cell Commun Signal. 2025 May 01. 23(1): 211

Targeting microglial NAAA-regulated PEA signaling counters inflammatory damage and symptom progression of post-stroke anxiety.

Tianyue Yin, Shuaijie Sun, Li Peng, Mengmeng Yang, Mengyu Li, Xinlu Yang, Fengyun Yuan, Hongrui Zhu, Sheng Wang.

  Post-stroke anxiety (PSA) manifests as anxiety symptoms after stroke, with unclear mechanisms and limited treatment strategies. Endocannabinoids, reported to mitigate fear, anxiety, and stress, undergo dynamic alterations after stroke linked to prognosis intricately. However, endocannabinoid metabolism in ischemic microenvironment and their associations with post-stroke anxiety-like behavior remain largely uncovered. Our findings indicated that endocannabinoid metabolism was dysregulated after stroke, characterized by elevated N-palmitoylethanolamide (PEA) hydrolase N-acylethanolamine-acid amidase (NAAA) in activated microglia from ischemic area, accompanied by rapid PEA exhaustion. Microglial PEA metabolite exhaustion is directly associated with more severe pathological damage, anxiety symptoms and pain sensitivity. Naaa knockout or pharmacological supplementation to boost PEA pool content can effectively promote stroke recovery and alleviate anxiety-like behaviors. In addition, maintaining PEA pool content in ischemic area reduces overactivated microglia by confronting against mitochondria dysfunction and inflammasome cascade triggered IL-18 release and diffusion to contralateral hemisphere. Meanwhile, maintenance of microglial PEA pool content in ischemic-damaged lesion can preserve contralateral vCA1 synaptic integrity, enhancing anxiolytic pBLA-vCA1Calb1+ circuit activity by alleviating microglial phagocytosis-mediated synaptic loss. Thus, we conclude that microglial NAAA-regulated lipid signaling in the ischemic focus remodels contralateral anxiolytic circuit to participate in post-stroke anxiety progression. Blocking PEA signaling breakdown promotes stroke recovery and mitigates anxiety-like symptoms.

Keywords:  Microglia; N-acylethanolamine acid amidase; N-palmitoylethanolamide; Post-stroke anxiety; Stroke

DOI:  https://doi.org/10.1186/s12964-025-02202-2
Elife. 2025 Apr 29. pii: RP97671. [Epub ahead of print]13

Microglia aging in the hippocampus advances through intermediate states that drive activation and cognitive decline.

Jeremy M Shea, Saul A Villeda.

  During aging, microglia - the resident macrophages of the brain - exhibit altered phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an activated state. Furthermore, we utilized single-cell RNA-Seq in conjunction with in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse models to demonstrate that microglia advancement through intermediate aging states drives transcriptional inflammatory activation and hippocampal-dependent cognitive decline.

Keywords:  aging; cognition; hippocampus; immunology; inflammation; microglia; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.97671
Front Immunol. 2025 ;16 1554999

The P2X7R-antagonist AFC-5128 ameliorates chronic experimental autoimmune encephalomyelitis in a preventive and therapeutic paradigm.

Robert Hoffrogge, Anna Karachunskaya, Neele Heitmann, Xiomara Pedreiturria, Katharina Klöster, Verian Bader, Konstanze F Winklhofer, Michael Hamacher, Bert Klebl, Ralf Gold, Klaus Dinkel, Ingo Kleiter, Simon Faissner.

   Background: Multiple sclerosis (MS) is characterized by chronic inflammation driven by central nervous system (CNS)-resident immune cells such as microglia, especially during the progressive phase of the disease. The P2X7 receptor (P2X7R), a risk protein for MS, is ubiquitously expressed on immune cells. AFC-5128, a CNS-penetrating small molecule inhibitor of P2X7R, is a promising agent for the treatment of autoimmune diseases such as MS.
Methods: In vitro, the effects on the calcium influx of primary murine microglia were assessed via Fluo-4 calcium imaging. In vivo, MOG35-55 immunized C57BL/6 mice were treated with AFC-5128, fingolimod (FTY) or vehicle in different treatment paradigms. The mice were scored daily. Microglial marker expression, immune cell phenotyping and serum cytokine analyses were performed via flow cytometry. Immune cell infiltration, demyelination and Iba1+/CD3+ cells were detected in spinal cord cross-sections. The effects of MOG35-55 T-cell restimulation were assessed in vitro.
Results: In vitro, treatment of primary microglia with 10 µM AFC-5128 reduced the influx of calcium following ATP stimulation (p<0.0001). In vivo, treatment of mice with AFC-5128 led to a reduction in overall EAE scores in acute and chronic EAE, with the best effects using 200 mg/kg body weight AFC-5128 (p<0.0001). Peripheral immune cell subsets (B cells, T cells and macrophages) and serum cytokine levels of chronic EAE mice treated in a therapeutic paradigm were not affected. While the expression of homeostasis markers of microglia in AFC-5128-treated mice was not affected, there was a trend toward lower expression of phagocytosis-associated markers. Late therapeutic treatment with AFC-5128 had only mild effects on chronic EAE.
Conclusion: The treatment of EAE mice with AFC-5128 improved acute and chronic EAE in different treatment paradigms, with positive effects on histological markers and slight modulation of microglial marker expression. Mechanistically, calcium influx of microglia was reduced following AFC-5128 treatment, which implies the ability of AFC-5128 to stabilize calcium homeostasis. Therefore, therapeutic inhibition of P2X7R via AFC-5128 has the potential for translation into a treatment of both relapsing and progressive forms of multiple sclerosis.

Keywords:  P2X7R; microglia; neuroinflammation; neuroprotection; progressive multiple sclerosis

DOI:  https://doi.org/10.3389/fimmu.2025.1554999
PLoS Pathog. 2025 Apr 28. 21(4): e1013126

Astrocyte-derived complement C3 facilitated microglial phagocytosis of synapses in Staphylococcus aureus-associated neurocognitive deficits.

Haifang Zhang, Qiyuan Jin, Jijie Li, Jiali Wang, Mengqi Li, Qiao Yin, Qi Li, Yuwan Qi, Lingling Feng, Liang Shen, Yuan Qin, Qifei Cong.

The presence of pathogens is a significant challenge in causing brain infections and tissue damage. There is growing evidence that pathogen infections are commonly associated with cognitive dysfunction and mental health problems, but the underlying mechanisms are not yet fully understood. Here, we found microglia and astrocyte activation, neuronal damage, synapse loss, and cognitive impairment in a Staphylococcus aureus (S. aureus) induced mouse model. An unbiased transcription profile of isolated microglia derived from S. aureus-infected mice identified the involvement of microglial phagosome and regulation of neurogenesis. Our findings indicate that the complement C1q and C3 are upregulated, and astroglial release of C3 activates microglia to phagocytose synapses. Blocking the C3-C3aR axis can improve microglial phagocytosis, thus rescuing synapse loss and cognitive impairment in infected mice. These results indicate that S. aureus induces synapse elimination and cognitive impairment by activating microglia and astrocytes through C3-C3aR signaling. This suggests a mechanism of complement signaling bridged crosstalk between astrocyte and microglia in the S. aureus-associated post-infectious synapse loss and cognitive dysfunction, and provide potential therapeutic targets for managing pathogen-associated brain infections.

DOI: https://doi.org/10.1371/journal.ppat.1013126
Immun Ageing. 2025 Apr 29. 22(1): 15

Chronic IL-21 drives neuroinflammation and promotes lipid accumulation in microglia.

Hugo Oyamada, Yinzhi Ying, Sudhanshu Agrawal, Aizhu Liu, Veedamali S Subramanian, Cleonice Alves de Melo Bento, Anshu Agrawal.

  Neuroinflammation is a key contributor to the onset and progression of neurodegenerative diseases, driven by factors such as viral infections, autoimmune disorders, and peripheral inflammation. However, the mechanisms linking peripheral inflammation or viral infections to neuroinflammation remain poorly understood, limiting the development of effective therapies. Proinflammatory cytokines are implicated in these processes but their effects on brain cells, including microglia, remain insufficiently characterized. Here, we demonstrate that IL-21, a proinflammatory cytokine elevated in autoimmune disorders, chronic viral infections, and Alzheimer's disease, activates microglia and promotes lipid accumulation within these cells. Young, healthy mice injected with IL-21 to mimic chronic exposure exhibited increased proinflammatory cytokine levels and microglial activation in the brain. Notably, microglia in these mice displayed enhanced lipid accumulation, accompanied by upregulation of lipid uptake receptors such as CD36 and TREM-2. These findings were corroborated using the human microglial cell line HMC-3, where IL-21 exposure similarly induced lipid accumulation and increased expression of CD36 and ApoE. Mechanistic investigations revealed that IL-21 upregulates HIF-1α, a transcription factor critical for lipid metabolism and lipid droplet formation. Additionally, we observed elevated IL-21 levels in the circulation of elderly individuals compared to younger counterparts, with IL-21 increases associated with CMV seropositivity. Aged mouse brains mirrored the microglial lipid accumulation and activation patterns seen in IL-21-injected mice. In summary, we identify a novel IL-21-driven mechanism involving lipid accumulation in microglia that contributes to neuroinflammation.

Keywords:  Aging; IL-21; Lipid; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12979-025-00510-2
Exp Neurol. 2025 Apr 24. pii: S0014-4886(25)00136-0. [Epub ahead of print]390 115272

Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques.

Sarah Kaye, Andrew Gold, Da Lin, Min Chen, Jiangjiang Zhu, Jie Gao.

  Hypercholesterolemia is a recognized comorbidity of Alzheimer's disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APPNL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APPNL-G-F;LDLR-/- (ALKO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a control diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.

Keywords:  Alzheimer's disease; Amyloid beta; Hypercholesterolemia; Microglia

DOI:  https://doi.org/10.1016/j.expneurol.2025.115272