bims-microg 2025-03-30 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–03–30
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Choroidal Neovascularization Is Suppressed With Activation of TREM2 in Mononuclear Phagocytes.
Akkermansia mono-colonization modulates microglia and astrocytes in a strain specific manner.
Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV.
How microglia contribute to the induction and maintenance of neuropathic pain.
Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5.
Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway.
The OLR1/NF-κB feedback loop exacerbates HIV-1 Tat-induced microglial inflammatory response and neuronal apoptosis.
Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.
Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes.
Microglial CARD19 ameliorates post-stroke neuroinflammation by stabilizing mitochondrial cristae.
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.
Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity.
Long-Term Minocycline Treatment Exhibits Enhanced Therapeutic Effects on Ischemic Stroke by Suppressing Inflammatory Phenotype of Microglia Through the EMB/MCT4/STING Pathway.
Dicer deficiency affects microglial function during demyelination and impairs remyelination.
Emerging roles of microglia and neuroinflammation in Huntington's disease: From pathophysiology to clinical trials.
Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination.
Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration.
ATP11B Modulates Microglial Lipid Metabolism and Alleviates Alzheimer's Disease Pathology.

Arterioscler Thromb Vasc Biol. 2025 Mar 27.

Choroidal Neovascularization Is Suppressed With Activation of TREM2 in Mononuclear Phagocytes.

Hitomi Yagi, Myriam Boeck, Katherine Neilsen, Jay Yang, Minji Ko, Yohei Tomita, Kazuno Negishi, Zhongjie Fu, Ye Sun, Lois E H Smith.

   BACKGROUND: Mononuclear phagocytes contribute to pathological angiogenesis in age-related macular degeneration, a leading worldwide cause of visual impairment. However, the mechanisms that orchestrate the functions of mononuclear phagocytes remain poorly understood. TREM2 (triggering receptor on myeloid cells 2) has been shown to be crucial for the activation of mononuclear phagocytes in atherosclerosis, fatty liver disease, and Alzheimer disease. The objective of this study was to investigate the role of TREM2 in pathological angiogenesis in age-related macular degeneration.
METHODS: C57BL/6J and Trem2 knockout mice were subjected to laser-induced choroidal neovascularization, a model of choroidal neovascular age-related macular degeneration. Purified bovine sulfatide and agonist anti-TREM2 antibody was used to activate TREM2 signaling. The expression of TREM2 or downstream signals were assessed with immunohistochemistry or qPCR. In vitro murine macrophage RAW264.7 cells were used to investigate the direct impact of sulfatide on inflammatory and phagocytic responses.
RESULTS: We found that pharmacological activation of TREM2 suppressed laser-induced choroidal neovessel formation. The activation of TREM2 in mononuclear phagocytes suppressed TNF (tumor necrosis factor) and subsequently promoted phagocytosis.
CONCLUSIONS: These findings demonstrate that activation of TREM2 in mononuclear phagocytes suppresses the proinflammatory response, promotes phagocytosis, and impedes choroidal neovessel formation. Our study provides insight into the critical role of TREM2 in pathological angiogenesis.

Keywords:  choroidal neovascularization; macrophages; macular degeneration; microglia; phagocytes

DOI:  https://doi.org/10.1161/ATVBAHA.124.321809
J Neuroinflammation. 2025 Mar 27. 22(1): 94

Akkermansia mono-colonization modulates microglia and astrocytes in a strain specific manner.

Luke A Schwerdtfeger, Toby B Lanser, Federico Montini, Thais Moreira, Danielle S LeServe, Laura M Cox, Howard L Weiner.

  Microglia and astrocytes are the primary glial cells in the central nervous system (CNS) and their function is shaped by multiple factors. Regulation of CNS glia by the microbiota have been reported, although the role of specific bacteria has not been identified. We colonized germ-free mice with the type strain Akkermansia muciniphila (AmT) and a novel A. muciniphila strain BWH-H3 (Am-H3) isolated from a subject with multiple sclerosis and compared to mice colonized with Bacteroides cellulosilyticus strain BWH-E5 (Bc) isolated from a healthy control subject. We then investigated the effect of these bacteria on microglia and astrocyte gene expression by RNA sequencing. We found altered gene expression profiles in brain microglia, with Akkermansia downregulating genes related to antigen presentation and cell migration. Furthermore, we observed strain specific effects, with Akkermansia H3 upregulating histone and protein binding associated genes and downregulating channel and ion transport genes. Astrocyte pathways that were altered by Akkermansia H3 mono-colonization included upregulation of proliferation pathways and downregulation in cytoskeletal associated genes. Furthermore, animals colonized with type strain Akkermansia and strain H3 had effects on the immune system including elevated splenic γδ-T cells and increased IFNγ production in CD4 + T cells. We also measured intestinal short chain fatty acids and found that both A. muciniphila strains produced proprionate while B. cellulosilyticus produced acetate, proprionate, and isovalerate. Taken together, our study shows that specific members of the intestinal microbiota influence both microglial and astroyctes which may be mediated by changes in short chain fatty acids and peripheral immune signaling.

Keywords:  Akkermansia; Astrocyte; Germ-free; Microglia; Mono-colonization; RNAseq

DOI:  https://doi.org/10.1186/s12974-025-03417-3
J Neuroinflammation. 2025 Mar 23. 22(1): 91

Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV.

Stephanie M Matt, Rachel Nolan, Samyuktha Manikandan, Yash Agarwal, Breana Channer, Oluwatofunmi Oteju, Marzieh Daniali, Joanna A Canagarajah, Teresa LuPone, Krisna Mompho, Kaitlyn Runner, Emily Nickoloff-Bybel, Benjamin Li, Meng Niu, Johannes C M Schlachetzki, Howard S Fox, Peter J Gaskill.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.

DOI: https://doi.org/10.1186/s12974-025-03403-9
Nat Rev Neurosci. 2025 Mar 24.

How microglia contribute to the induction and maintenance of neuropathic pain.

Marzia Malcangio, George Sideris-Lampretsas.

Neuropathic pain is a debilitating condition caused by damage to the nervous system that results in changes along the pain pathway that lead to persistence of the pain sensation. Unremitting pain conditions are associated with maladaptive plasticity, disruption of neuronal activity that favours excitation over inhibition, and engagement of immune cells. The substantial progress made over the last two decades in the neuroimmune interaction research area points to a mechanistic role of spinal cord microglia, which are resident immune cells of the CNS. Microglia respond to and modulate neuronal activity during establishment and persistence of neuropathic pain states, and microglia-neuron pathways provide targets that can be exploited to attenuate abnormal neuronal activity and provide pain relief.

DOI: https://doi.org/10.1038/s41583-025-00914-5
Cell Mol Life Sci. 2025 Mar 26. 82(1): 131

Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5.

Alejandro Montilla, Alazne Zabala, Ibai Calvo, Marina Bosch-Juan, Irene Tomé-Velasco, Paloma Mata, Mirjam Koster, Amanda Sierra, Susanne M Kooistra, Federico N Soria, Bart J L Eggen, Olatz Fresnedo, José Andrés Fernández, Vanja Tepavcevic, Carlos Matute, María Domercq.

  Interferon regulatory factor 5 (IRF5) is a transcription factor that plays a role in orchestrating innate immune responses, particularly in response to viral infections. Notably, IRF5 has been identified as a microglia risk gene linked to multiple sclerosis (MS), but its specific role in MS pathogenesis remains unclear. Through the use of Irf5-/- mice, our study uncovers a non-canonical function of IRF5 in MS recovery. Irf5-/- mice exhibited increased damage in an experimental autoimmune encephalomyelitis (EAE) model and demonstrated impaired oligodendrocyte recruitment into the lesion core following lysolecithin-induced demyelination. Transcriptomic and lipidomic analyses revealed that IRF5 has a role in microglia-mediated myelin phagocytosis, lipid metabolism, and cholesterol homeostasis. Indeed, Irf5-/- microglia phagocytose myelin, but myelin debris is not adequately degraded, leading to an accumulation of lipid droplets, cholesterol esters, and cholesterol crystals within demyelinating lesions. This abnormal buildup can hinder remyelination processes. Importantly, treatments that promote cholesterol transport were found to reduce lipid droplet accumulation and mitigate the exacerbated damage in Irf5-/- mice with EAE. Altogether, our study identified the antiviral transcription factor IRF5 as a key transcriptional regulator of lipid degradation and cholesterol homeostasis and suggest that loss of IRF5 function leads to pathogenic lipid accumulation in microglia, thereby obstructing remyelination. These data and the fact that Irf5 polymorphisms are significantly associated with MS, highlight IRF5 as a potential therapeutic target to promote regenerative responses.

Keywords:  Demyelination; IRF5; Lipid homeostasis; Microglia; Multiple sclerosis; Remyelination

DOI:  https://doi.org/10.1007/s00018-025-05648-2
J Alzheimers Dis. 2025 Mar 28. 13872877251329439

Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway.

Yanyu Zhai, Kaili Lu, Yuan Yuan, Ziyao Zhang, Lixia Xue, Fei Zhao, Xiaofeng Xu, Hongmei Wang.

  BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.

Keywords:  APP/PS1; Alzheimer's disease; NF-κB pathway; neuroinflammation; semaglutide

DOI:  https://doi.org/10.1177/13872877251329439
J Neurovirol. 2025 Mar 26.

The OLR1/NF-κB feedback loop exacerbates HIV-1 Tat-induced microglial inflammatory response and neuronal apoptosis.

Qifei Zhang, Wenhua Tao, Jing Wang, Meijuan Qian, Mingming Zhou, Lin Gao.

  Oxidized low density lipoprotein receptor 1 (OLR1), a type II integral membrane glycoprotein, is involved in multiple neurological diseases. However, the roles and mechanisms of OLR1 in HIV-associated neurocognitive disorder (HAND) remain unclear. In the central nervous system, Transactivator of transcription (Tat) induces inflammatory response in microglia, thereby leading to neuronal apoptosis. In the present study, we demonstrated that OLR1 expression was upregulated during ectopic expression of Tat or soluble Tat stimulus in BV-2 microglial cells. Moreover, OLR1 signaling was proved to facilitate Tat-triggered inflammatory response and alleviated the microglia-derived conditioned media-mediated HT-22 neural cells apoptosis in a NF-κB-dependent manner. Conversely, Tat augmented OLR1 expression via NF-κB signaling pathway. Finally, in mouse models, we determined that silencing of OLR1 significantly ameliorated Tat‑induced neuroinflammation and hippocampal neuronal death. Taken together, our study clarifies the potential role of the OLR1/NF-κB feedback loop in Tat-induced microglial inflammatory response and neuronal apoptosis, which could be a novel therapeutic target for relief of HAND.

Keywords:  HIV-associated neurocognitive disorder; Microglia; NF-κB; Neuroinflammation; OLR1; Tat

DOI:  https://doi.org/10.1007/s13365-025-01249-8
Immunity. 2025 Mar 18. pii: S1074-7613(25)00091-3. [Epub ahead of print]

Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.

Matija Zelic, Anna Blazier, Fabrizio Pontarelli, Michael LaMorte, Jeremy Huang, Ozge E Tasdemir-Yilmaz, Yi Ren, Sean K Ryan, Cynthia Shapiro, Caroline Morel, Pavithra Krishnaswami, Mikhail Levit, Disha Sood, Yao Chen, Joseph Gans, Xinyan Tang, Jennifer Hsiao-Nakamoto, Fen Huang, Bailin Zhang, James D Berry, Dinesh S Bangari, Giorgio Gaglia, Dimitry Ofengeim, Timothy R Hammond.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation is prominent in ALS, but the cell state dynamics and pathways driving disease remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on the inflammation and cell death regulator receptor-interacting protein kinase 1 (RIPK1) and the necroptotic cell death pathway. In superoxide dismutase 1 (SOD1)G93A mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human induced pluripotent stem cell (iPSC)-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation in vitro and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of people with ALS. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

Keywords:  ALS; RIPK1; astrocytes; microglia; neuroinflammation; single-nucleus RNA-seq

DOI:  https://doi.org/10.1016/j.immuni.2025.02.024
Nat Commun. 2025 Mar 22. 16(1): 2821

Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes.

Kai He, Xue Dong, Tianjing Yang, Ziqi Li, Yuming Liu, Jing He, Meng Wu, Selena Wei-Zhang, Parhat Kaysar, Bohao Cui, Xueming Yao, Li Zhang, Wei Zhou, Heping Xu, Jun Wei, Qiang Liu, Junhao Hu, Xiaohong Wang, Hua Yan.

Age-related macular degeneration (AMD) is a prevalent neuroinflammation condition and the leading cause of irreversible blindness among the elderly population. Smoking significantly increases AMD risk, yet the mechanisms remain unclear. Here, we investigate the role of Sema4D-PlexinB1 axis in the progression of AMD, in which Sema4D-PlexinB1 is highly activated by smoking. Using patient-derived samples and mouse models, we discover that smoking increases the presence of Sema4D on the surface of CD8+ T cells that migrate into the choroidal neovascularization (CNV) lesion via CXCL12-CXCR4 axis and interact with its receptor PlexinB1 on choroidal pericytes. This leads to ROR2-mediated PlexinB1 phosphorylation and pericyte activation, thereby disrupting vascular homeostasis and promoting neovascularization. Inhibition of Sema4D reduces CNV and improves the benefit of anti-VEGF treatment. In conclusion, this study unveils the molecular mechanisms through which smoking exacerbates AMD pathology, and presents a potential therapeutic strategy by targeting Sema4D to augment current AMD treatments.

DOI: https://doi.org/10.1038/s41467-025-58074-0
Neural Regen Res. 2025 Mar 25.

Microglial CARD19 ameliorates post-stroke neuroinflammation by stabilizing mitochondrial cristae.

Yujie Hu, Liwen Zhu, Chao Zhou, Qi Li, Huiya Li, Shiji Deng, Shengnan Xia, Haiyan Yang, Xinyu Bao, Pinyi Liu, Yun Xu.

ABSTRACT: Microglia are the first immune cells that are activated in the brain following ischemic stroke. Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke. Caspase activation and recruitment domain 19 (CARD19) is involved in innate immune response and inflammatory response, which are also important functions of microglia. However, the role of CARD19 in microglial biology and ischemic stroke remains unknown. Here, we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue, as well as in an in vitro model of microglial activation. Remarkably, conditional knockdown of Card19 in microglia promoted poststroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke. Mechanistically, we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components, while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae, leading to an exaggerated pro-inflammatory response. Thus, our findings suggest that preserving mitochondrial cristae, by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00923
Mol Neurodegener. 2025 Mar 27. 20(1): 37

Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.

Eun Sun Jung, Hayoung Choi, Inhee Mook-Jung.

  Alzheimer's disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation and glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts as an energy sensor, coordinating lipid and glucose metabolism. TREM2 and APOE regulate microglial lipid homeostasis, influencing Aβ clearance and immune responses. LPL and ABCA7, both associated with AD risk, modulate lipid processing and cholesterol transport, linking lipid metabolism to neurodegeneration. PPARG further supports lipid metabolism by regulating microglial inflammatory responses. Amino acid metabolism also contributes to microglial function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked to AD pathology. Additionally, glucose-6-phosphate dehydrogenase regulates the pentose phosphate pathway, maintaining redox balance and immune activation. Dysregulated glucose and lipid metabolism, influenced by genetic variants such as APOE4, impair microglial responses and exacerbate AD progression. Recent findings highlight the interplay between metabolic regulators like REV-ERBα, which modulates lipid metabolism and inflammation, and Syk, which influences immune responses and Aβ clearance. These insights offer promising therapeutic targets, including strategies aimed at HIF-1α modulation, which could restore microglial function depending on disease stage. By integrating metabolic, immune, and genetic factors, this review underscores the importance of microglial immunometabolism in AD. Targeting key metabolic pathways could provide novel therapeutic strategies for mitigating neuroinflammation and restoring microglial function, ultimately paving the way for innovative treatments in neurodegenerative diseases.

Keywords:  APOE; Aβ; HIF; Hexokinase; Immunometabolism; Metabolic reprogramming; Microglia; Neuroinflammation; TREM2; Tau

DOI:  https://doi.org/10.1186/s13024-025-00825-0
Nat Commun. 2025 Mar 22. 16(1): 2840

Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity.

Gabriel L McKinsey, Nicolas Santander, Xiaoming Zhang, Kilian L Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos O Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E S Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas D Arnold.

Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers Smad2 and Smad3 have a less polarized dysmature phenotype and correspondingly less severe neuromotor dysfunction. Our study describes the spatio-temporal regulation of TGFβ activation and signaling in the brain necessary to promote microglial development, and provides evidence for the adoption of microglial developmental signaling pathways in brain injury or disease.

DOI: https://doi.org/10.1038/s41467-025-57684-y
CNS Neurosci Ther. 2025 Mar;31(3): e70328

Long-Term Minocycline Treatment Exhibits Enhanced Therapeutic Effects on Ischemic Stroke by Suppressing Inflammatory Phenotype of Microglia Through the EMB/MCT4/STING Pathway.

Bo Cheng, Shangqi Liu, Ling Gao, Ning Xin, Zhenying Shang, Ziwen Zhu, Yang Yang, Rui Ma, Zixiang Xu, Jing Liu, Dunjing Wang.

   BACKGROUND: Neuroinflammation caused by excessive activation of microglia is a significant cause of poor prognosis in ischemic stroke patients. Minocycline, a microglial cell inhibitor, has neuroprotective effects in stroke, but its optimal treatment duration and specific mechanisms of action remain unclear. This study aimed to compare the efficacy of different minocycline treatment durations on stroke and explore their mechanisms of action.
METHODS: We investigated the effects of various durations of minocycline treatment on microglial polarization using cellular and animal models. The mechanisms of long-term minocycline therapy for neuroprotective effects were explored through in vitro and in vivo experiments.
RESULTS: In stroke models, long-term minocycline treatment showed a stronger inhibitory effect on neuroinflammation and improved neuron viability compared with short-term treatment. Further in vitro and in vivo results indicated that long-term minocycline treatment downregulated microglial glycolysis levels through the EMB/MCT4 axis, promoting the transformation of microglia to an anti-inflammatory phenotype by inhibiting the activation of the STING pathway, thereby improving post-stroke neuroinflammation.
CONCLUSION: Long-term minocycline therapy exerts neuroprotective effects in ischemic stroke by regulating the EMB/MCT4/STING axis and inhibiting the inflammatory phenotype of microglia through downregulating cellular glycolysis levels. Extending the treatment duration of minocycline appropriately may further improve ischemic stroke outcomes.

Keywords:  glycolysis; ischemic stroke; microglia; minocycline; neuroinflammation

DOI:  https://doi.org/10.1111/cns.70328
Neurobiol Dis. 2025 Mar 20. pii: S0969-9961(25)00095-6. [Epub ahead of print]208 106879

Dicer deficiency affects microglial function during demyelination and impairs remyelination.

Ajai Tripathi, Nagendra Kumar Rai, Aaron Perles, Haley Courtney, Claire Jones, Adya Sapra, Jason Plemel, Ranjan Dutta.

  Microglia are essential regulators of central nervous system (CNS) homeostasis, playing key roles in demyelination and remyelination. Dysregulated microglial activity contributes to pathological inflammation and impaired repair processes in demyelinating diseases. Here, we investigate the role of Dicer1, a critical enzyme in microRNA biogenesis, in affecting microglial function, demyelination, and remyelination. Loss of Dicer1 in microglia resulted in amplified inflammatory responses, defective myelin debris clearance, and disruption of metabolic homeostasis, leading to exacerbated demyelination and delayed remyelination. Transcriptomic analysis revealed significant upregulation of inflammatory pathways, including interferon signaling and JAK/STAT activation, alongside a loss of homeostatic microglial gene expression. Protein-level validation confirmed sustained secretion of pro-inflammatory cytokines such as IFN-γ, IL-16, and CXCL12, creating a chronic inflammatory environment that impaired remyelination. Furthermore, Dicer1-deficient microglia failed to support oligodendrocyte progenitor cells (OPCs) differentiation/maturation, with increased apoptosis of mature oligodendrocytes (OLs), contributing to remyelination failure. These findings identify Dicer1 as a critical regulator of microglial homeostasis and inflammation resolution, highlighting its potential as a therapeutic target to mitigate inflammation and promote repair in demyelinating diseases.

Keywords:  Cytokines; Demyelination; Dicer1; Inflammation; Microglia; Remyelination; microRNA

DOI:  https://doi.org/10.1016/j.nbd.2025.106879
J Huntingtons Dis. 2025 Mar 28. 18796397251330144

Emerging roles of microglia and neuroinflammation in Huntington's disease: From pathophysiology to clinical trials.

Muna Abedrabbo, Pardis Kazemian, Colúm Connolly, Blair R Leavitt.

  Microglia, the resident immune cells of the central nervous system, play a pivotal role in the response to Huntington's disease (HD) pathology. Through both cell-autonomous mechanisms and exposure to external pathogenic stimuli, microglia transition from a resting to an activated state, producing pro-inflammatory cytokines and chemokines that mediate inflammation. While this inflammatory response attempts to have a neuroprotective compensatory effect, chronic microglial activation exacerbates neuroinflammation, neurodegeneration and contributes to disease progression. Evidence from postmortem analyses and neuroimaging studies indicates that activated microglia are present in various stages of HD, correlating with neuronal degeneration and clinical symptoms. Enhanced microglial activation has been identified as an early predictor of disease onset, particularly in premanifest HD, highlighting the potential of targeting microglial pathways for therapeutic interventions. This review explores microglia's dual role in HD pathophysiology, exploring their contributions to both neuroinflammation and neuroprotection. It also examines recent advances in clinical trials aimed at modulating microglial activity, paving the way for novel therapeutic strategies to alter disease progression and improve patient outcomes.

Keywords:  Huntington's disease; anti-inflammatory therapies; huntingtin; microglia; neurodegeneration; neuroinflammation; neurological disease

DOI:  https://doi.org/10.1177/18796397251330144
Mol Metab. 2025 Mar 20. pii: S2212-8778(25)00035-3. [Epub ahead of print] 102128

Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.

L Stilgenbauer, Q Chen, D Pungi, N James, H Jayarathne, L Koshko, S Scofield, K Zhang, M Sadagurski.

   BACKGROUND: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.
OBJECTIVES: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.
METHODS: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.
RESULTS: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.
CONCLUSIONS: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.

Keywords:  ER stress; Hypothalamic inflammation; Hypothalamus; Microglia; Neuroinflammation; UPR

DOI:  https://doi.org/10.1016/j.molmet.2025.102128
Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2426786122

Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination.

Jinchao Hou, Roberta Magliozzi, Yun Chen, Junjie Wu, John Wulf, Gregory Strout, Xiangming Fang, Marco Colonna.

  We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here, we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases of the CPZ model and analyzed the impact of the antibody treatment on myelination and gene expression in single cells. We found that blocking TREM2 depleted a distinct population of microglia with high expression of the transcription factor MAFB during remyelination. The loss of these MAFB-high microglia was linked to impaired generation of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that is associated with myelin repair. This finding has significant implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a promising therapeutic approach for myelin repair.

Keywords:  TREM2; microglia; multiple sclerosis; myelin; transcription factor

DOI:  https://doi.org/10.1073/pnas.2426786122
J Neuroinflammation. 2025 Mar 23. 22(1): 93

Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration.

Kai Chen, Fuyao Li, Shuwen Zhang, Yixing Chen, Tadafumi C Ikezu, Zonghua Li, Yuka A Martens, Wenhui Qiao, Axel Meneses, Yiyang Zhu, Gisela Xhafkollari, Guojun Bu, Na Zhao.

  TREM2, a microglia-specific receptor, is strongly associated with Alzheimer's disease (AD) risk, mediating microglial responses to amyloid pathology critical to AD development. However, its role in tau pathology and neurodegeneration remains unclear. Using the PS19 tauopathy mouse model with inducible overexpression of human wild-type TREM2 (TREM2-WT) or the R47H variant (TREM2-R47H), we show that increasing TREM2-WT expression modestly reduces soluble phosphorylated tau levels and mildly preserves neuronal integrity. Single-cell RNA sequencing reveals that TREM2-WT robustly enhances microglial activation, characterized by a disease-associated microglia (DAM) signature. In contrast, TREM2-R47H overexpression exhibits a loss-of-function phenotype, with no significant impact on tau levels, neurodegeneration, or microglial activation. These findings highlight the role of TREM2 in modulating microglial activity and its influence on tau pathology and neurodegeneration, providing important insights for the future development of therapies targeting TREM2 or microglial pathways in AD or other tauopathies.

Keywords:  Alzheimer’s disease; Microglia; R47H variant; TREM2; Tau pathology; Transcriptomics

DOI:  https://doi.org/10.1186/s12974-025-03420-8
MedComm (2020). 2025 Apr;6(4): e70139

ATP11B Modulates Microglial Lipid Metabolism and Alleviates Alzheimer's Disease Pathology.

Yuchen Zhang, Shibo Zhang, Xuyu Zhao, Peiru Wu, Yiwei Ying, Lingling Wu, Junyi Zhuang, Zixin Chen, Yufan Chao, Xin Dong, Robert Chunhua Zhao, Jiao Wang.

  Abnormal lipid metabolism in microglia leads to the formation of pathological lipid droplets (LDs), a phenomenon also observed in neurodegenerative diseases such as Alzheimer's disease (AD). The abnormal accumulation of LDs disrupts normal cellular function and exacerbates the pathological process of AD. ATP11B is a P4-ATPase and the expression of Atp11b changes in the brain of patients with AD and diseases of lipid metabolism. The present study aimed to explore the regulatory role of ATP11B in microglial lipid metabolism and assess the potential of ATP11B as a therapeutic target for AD. Atp11b deficiency caused excessive fatty acid uptake and activated the PPAR signaling pathway, resulting in abnormal synthesis of neutral lipids and mitochondrial energy metabolism in microglia. Further results showed that Atp11b deficiency led to the accumulation of pathological LDs in microglia and AD mice. Conversely, overexpression of Atp11b alleviated exploratory behavior impairment, learning and memory impairment, LD accumulation, beta-amyloid (Aβ) deposition, and inflammatory response in the brain of AD mice. These findings provide important clues for a better understanding of the pathogenesis of AD and for developing novel therapeutic strategies.

Keywords:  ATP11B; Alzheimer's disease; lipid droplets; lipid metabolism; microglia

DOI:  https://doi.org/10.1002/mco2.70139