bims-microg 2026-03-29 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–03–29
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Bacillus cereus Induces Necroptosis in Microglia via the RIPK1/3-MLKL Pathway.
The influence of TLR4 signaling on retinal ganglion cell survival and angiogenic response in a mouse model of oxygen-induced retinopathy.
Complement, Inflammasome, and Microglial Crosstalk in Glaucoma: From Neurodegeneration to Immune-Based Precision Therapy.
Immunometabolic Regulation of Neuroinflammation in Retinitis Pigmentosa: Roles of Microglia, Müller Glia, and Regulated Cell Death.
Targeting the IRE1α/JNK-autophagy axis in microglia attenuates retinal neovascularization in oxygen-induced retinopathy.
Complement receptor 3 (CR3)-dependent microglial synapse elimination drives Parkinson's disease pathogenesis in systemic inflammation.
Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk.
Comprehensive single-cell transcriptomic atlas of microglia in Alzheimer's disease mouse models.
MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and are Clinically Relevant Across Central Nervous System Disorders.
The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation.
Somatostatin-induced modulation of microglial activity contributes to mitigating Alzheimer's disease pathology.
Microglia promote vascular remodeling in a mouse model of chronic stress.
Microglial PRMT2IP alleviates ischemia-induced brain injury.
Microglia-mediated protection against Alzheimer's disease pathology and detrimental effects in white matter revealed by Ptpn6 deletion.
Polymersomes preventing brain infiltration of CD177+ neutrophils to mitigate hemorrhagic transformation post-tPA thrombolysis.
Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination.
A transcriptomic microglia taxonomy across mouse and human pathologies.
Oligodendrocyte precursor cells-microglia crosstalk via BMP4 drives microglial neuroprotective response and mitigates Alzheimer's disease.

Microbiologyopen. 2026 Apr;15(2): e70276

Bacillus cereus Induces Necroptosis in Microglia via the RIPK1/3-MLKL Pathway.

Jing Yang, Bianjin Sun, Huijing Xu, Yangyang Shen, Huili Ye, Qiheng Yuan, Siwen Chen, Meiqin Zheng.

  Bacillus cereus endophthalmitis is a rapidly progressing intraocular infection that often results in poor visual outcomes due to extensive retinal damage. Microglia are resident innate immune cells in the brain and retina that play critical roles in neurological and ocular diseases. To investigate the functional role and mechanisms of microglia during B. cereus infection, we established an in vitro microglial infection model using murine BV2 and human HMC3 cells. B. cereus infection reduced microglial viability and induced membrane rupture. Transcriptome analysis revealed enrichment of inflammatory and cell death. Flow cytometric screening identified that the RIPK1 inhibitor Nec-1 rescued cell death. Mechanistically, B. cereus increased phosphorylation of RIPK3 and MLKL, which was abolished by Nec-1. Moreover, Nec-1 suppressed B. cereus-induced secretion of IL-1β, IL-6, and TNF-α. In summary, this study demonstrates that B. cereus induces microglial necroptosis by activating the RIPK3/MLKL pathway, providing a new mechanism for neuroinflammation caused by related infections.

Keywords:  Bacillus cereus; inflammatory response; microglia; necroptosis

DOI:  https://doi.org/10.1002/mbo3.70276
Biochem Biophys Rep. 2026 Jun;46 102550

The influence of TLR4 signaling on retinal ganglion cell survival and angiogenic response in a mouse model of oxygen-induced retinopathy.

Yasunari Munemasa.

   Purpose: Retinopathy of prematurity (ROP) is a critical concern in neonatal care and potentially leads to vision impairment. Despite advancements in anti-VEGF treatments, the mechanisms driving pathological vitreoretinal neovascularization remain unclear. I examined the role of Toll-like receptor 4 (TLR4) in modulating inflammatory cytokines, angiogenesis, and neuronal cell protection in a mouse model of oxygen-induced retinopathy (OIR).
Materials and methods: C57BL/6J TLR4-/- mice were subjected to OIR by exposure to 75% oxygen from postnatal days 7 to 12 (P7 to P12) following approved protocols. I used immunohistochemistry to assess TLR4 expression at P19, real-time quantitative PCR for proinflammatory cytokines at P19, ex vivo fluorescent vascular imaging to evaluate retinal vascular changes at P19, and retinal neuronal cells death evaluated by whole-mounted retina stained with cresyl violet at P47. Statistical significance was determined using one-way ANOVA (p < 0.05).
Results: Immunofluorescence demonstrated TLR4 expression in microglia in OIR retinas of wild-type mice but not in controls. Real-time PCR revealed significant upregulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP1) in OIR retinas, which was mitigated in TLR4-/- mice. Retinal angiogenesis significantly increased in wild-type OIR mice, whereas TLR4 knockdown inhibited these changes. Additionally, OIR caused approximately 30% neuronal cell death in the retinal ganglion cell layer, which was largely prevented in the TLR4-/- mice.
Conclusions: These findings underscore TLR4's pivotal role in the regulation of inflammatory responses and angiogenesis in ROP. Targeting TLR4 may represent a novel therapeutic approach to preserve retinal integrity and improve visual outcomes in at-risk populations, particularly in premature infants.

Keywords:  Retina; Retinopathy of prematurity; Toll-Like Receptor 4 (TLR4)

DOI:  https://doi.org/10.1016/j.bbrep.2026.102550
Life (Basel). 2026 Feb 24. pii: 368. [Epub ahead of print]16(3):

Complement, Inflammasome, and Microglial Crosstalk in Glaucoma: From Neurodegeneration to Immune-Based Precision Therapy.

Tony Yihao Chen, Na Wu, Xinghuai Sun.

  Glaucoma is no longer viewed solely as a pressure-mediated optic neuropathy but as a chronic neurodegenerative disease with a strong immune component. Across experimental models and patient samples, convergent inflammatory circuitry complement activation, NLRP3 inflammasome signaling, and microglial reactivity emerge as a central driver of retinal ganglion cell (RGC) dysfunction and death. Local complement upregulation (C1q, C3, C5) in the retina and optic nerve head (ONH) promotes aberrant synaptic tagging, phagoptosis, and membrane attack complex stress. In parallel, biomechanical strain, ischemia, mitochondrial damage, and danger-associated molecular patterns prime and activate the NLRP3 inflammasome in microglia, astrocytes, and ONH cells, leading to caspase-1 activation, IL-1β/IL-18 maturation, and pyroptotic or apoptotic injury. Microglia integrate these cues, shifting from early protective surveillance to chronic maladaptive states that amplify complement and inflammasome outputs. This review synthesizes mechanistic links within the complement NLRP3 microglia axis, considers systemic and adaptive immune contributions, and proposes a translational framework for immune-based clinical stratification. The literature for this review was identified through searches of PubMed, Web of Science, and Scopus using combinations of the terms 'glaucoma', 'complement', 'inflammasome', 'NLRP3', 'microglia', and 'neuroinflammation'. Priority was given to recent experimental, translational, and clinical studies. We then evaluate emerging immunomodulatory therapies, complement inhibitors, inflammasome blockers, microglial state reprogrammers, cytokine biologics, and cell-derived immunoregulatory approaches, highlighting biomarkers and trial design needs. An immune systems view of glaucoma enables precision neuroprotection for patients who progress despite controlled intraocular pressure.

Keywords:  NLRP3 inflammasome; complement; glaucoma; microglia; neuroinflammation; precision medicine; retinal ganglion cells

DOI:  https://doi.org/10.3390/life16030368
Biomolecules. 2026 Feb 28. pii: 364. [Epub ahead of print]16(3):

Immunometabolic Regulation of Neuroinflammation in Retinitis Pigmentosa: Roles of Microglia, Müller Glia, and Regulated Cell Death.

Yijing Yang, Pai Zhou, Ying Deng, Qinghua Peng.

  Chronic neuroinflammation is increasingly implicated in the progression of neurodegenerative diseases, yet the mechanisms linking metabolic stress, innate immune activation, and neuronal vulnerability remain incompletely defined. Retinitis pigmentosa (RP), despite its genetic heterogeneity, exhibits convergent inflammatory and metabolic alterations during disease progression, providing a useful model for studying immune-mediated neurodegeneration. This review summarizes current evidence from experimental models of retinal degeneration and human retinal studies to examine how sustained neuroinflammation is established in RP. We focus on the coordinated roles of retinal microglia and Müller glia in sensing photoreceptor stress and shaping the inflammatory microenvironment. Microglia are activated early in disease and contribute to progression through inflammatory signaling, phagoptosis, metabolic adaptation, and inflammasome-associated pathways. Müller glia, in turn, modulate metabolic homeostasis and propagate inflammatory signals across retinal layers. We also discuss how stress-responsive regulatory pathways, including p53-associated signaling, influence redox balance, iron handling, and inflammatory persistence without acting as primary apoptotic drivers. Together, these findings support a model in which chronic immunometabolic dysregulation contributes to retinal degeneration and highlight inflammation-related processes as potential targets for mutation-independent therapeutic strategies.

Keywords:  microglia; neuroinflammation; p53; retinal degeneration

DOI:  https://doi.org/10.3390/biom16030364
Free Radic Biol Med. 2026 Mar 24. pii: S0891-5849(26)00247-9. [Epub ahead of print]250 99-115

Targeting the IRE1α/JNK-autophagy axis in microglia attenuates retinal neovascularization in oxygen-induced retinopathy.

Hanwen Huang, Sha Gao, Shuang Gao, Na Li, Yumeng Zhang, Yanuo Wang, Xi Shen.

   PURPOSE: To investigate the role of IRE1α/JNK-Autophagy Axis on neovascular retinopathy, which will ultimately lead to irreversible vision loss without timely and effective intervention. Despite recent studies indicating that Endoplasmic Reticulum Stress (ERS) and autophagy are both associated with retinal neovascularization, their interaction and underlying molecular mechanisms remain unclear.
METHODS: Bioinformatics analysis of the GSE102485 dataset was conducted to evaluate gene level differences between patients with neovascular retinopathy and controls. The oxygen-induced retinopathy (OIR) mouse model was established to explore the role of IRE1α/JNK pathway in retinal microglia and its effect on neovascularization. The model was induced by exposing P7 mice to 75% oxygen for 5 days, followed by normoxia. IRE1α/JNK pathway activation was assessed using Western-blot, PCR and immunofluorescence. Primary retinal microglia were extracted and cultured under hypoxia to mimic the in vivo environment. The roles of IRE1α/JNK pathway on autophagy of retinal microglia were evaluated via Western-blot, immunofluorescence and Primary retinal microglia were transduced with an mRFP-GFP-LC3 adenovirus to visualize autophagosomes and autolysosomes. Primary microglia subjected to different treatments were co-cultured with HRMVECs, and tube formation assays were performed on the latter. In vivo, intravitreal injections of the IRE1 inhibitor 4μ8C or the IRE1 agonist IXA4, with/without the autophagy inhibitor bafilomycin A1 were administered. In vitro, primary microglia were treated with 4μ8C or IXA4, with/without bafilomycin A1.
RESULTS: Bioinformatics analysis revealed Gene ERN1 upregulated in patients with neovascular retinopathy, and pathways downstream of ERN1 showed enrichment in autophagy. In the OIR model, a significant activation of the IRE1α/JNK pathway was observed, reaching its peak on postnatal day 17, which coincided with increased levels of LC3AB and vascular endothelial growth factor A (VEGF-A). The compound 4μ8C was effective in suppressing IRE1α/JNK activation and autophagy activity, as well as VEGF-A level, thereby inhibiting retinal neovascularization in OIR mice. In vitro, we also observed upregulated levels of p-IRE1, p-JNK and LC3AB protein and decreased level of p62 protein in cultured retinal microglia exposed to hypoxia for 12h. However, 4μ8C attenuated these effects, leading to a decrease in VEGF-A secretion. Furthermore, IXA4, a highly selective IRE1 activator, was found to enhance autophagy activity and VEGF-A expression in retinal microglia both in vivo and in vitro. Also, IXA4 treatment further promoted retinal neovascularization in OIR mice. However, these effects were inhibited by bafilomycin A1, an autophagy inhibitor.
CONCLUSIONS: These findings demonstrates that activation of IRE1α/JNK pathway under hypoxic conditions in retinal microglia promotes RNV via enhancing autophagy activity., highlighting the potential of IRE1α/JNK -Autophagy Axis as a promising therapeutic target for neovascularization related retinopathy.

Keywords:  Autophagy; Endoplasmic reticulum stress; IRE1α/JNK signaling pathway; OIR mouse model; Retinal microglia; Retinal neovascularization

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.056
Cell Death Dis. 2026 Mar 25.

Complement receptor 3 (CR3)-dependent microglial synapse elimination drives Parkinson's disease pathogenesis in systemic inflammation.

Lei Cai, Yihe Zhang, Jiayi Li, Lamei Hu, Qinghao Meng, Jingyi Shao, Haotian Deng, Yiying Liu, Jiaqi Liu, Yue Liang, Nanshan Song, Jianhua Ding, Yi Fan, Ming Lu, Yinquan Fang, Gang Hu.

Although systemic inflammation has been implicated in PD pathogenesis, the underlying mechanisms remain poorly understood. In this study, we investigate the pathological events in a systemic inflammation-induced PD mouse model. We demonstrate that synaptic loss in the midbrain occurs as early as 1 day after the final lipopolysaccharide (LPS) administration, preceding dopaminergic (DA) neuron degeneration, which was observed only at later stages (14 days). Early microglial activation in the midbrain is detected, accompanied by excessive synaptic engulfment, suggesting a critical role of microglia-dependent synapse elimination in PD pathogenesis. Furthermore, we identify the complement receptor 3 (CR3) as a key mediator of microglial synaptic engulfment, revealing that its inhibition rescues synaptic integrity and prevents neurodegeneration. Our results contribute to a deeper understanding of early events of PD progression driven by systemic inflammation and provide early intervention strategies targeting microglial complement signaling to halt PD progression.

DOI: https://doi.org/10.1038/s41419-026-08557-9
Mol Psychiatry. 2026 Mar 26.

Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk.

Jing Wu, Xingyu Zhou, Tiandong Luo, Xin Wang, Hongzhou Zuo, Ruijing Yang, Ruimin Tian, Yiyuan Wu, Yang Wu, Wenxia Jiang, Yunpeng Wang, Jie Yang, Yu Huang, Jianping Zhang, Yifan Li, Ping Liu, Xunmin Tan, Minghao Yuan, Ma-Li Wong, Julio Licinio, Peng Zheng.

Major depressive disorder (MDD) is a major psychiatric condition associated with neuroimmune dysregulation. Microglia, the principal innate immune cells of the central nervous system, have been implicated in MDD. Nevertheless, the specific subpopulations involved and the mechanisms that govern their responses are still elusive. Here, we found that gut microbiota intervention using bedding from control non-stressed mice reverses chronic unpredictable mild stress (CUMS)-induced alterations in behavior. Using CD45+ immune cell sorting and single-cell RNA sequencing (scRNA-seq), we built an atlas of brain-resident microglia and non-microglial immune cells in the central and peripheral compartments. CUMS primarily induced transcriptional alterations in microglia and monocytes, while the reversed changes induced by bedding exchange mainly detected in microglia (85%). Among the microglial subtypes, homeostatic microglia 2 (HM2) primarily responded to CUMS. HM2 shaped microglial states through activation trajectory: the HM2→chemokine-related microglia 3→inflame microglia 1, which could be reversed by bedding exchange. Brain Mdcs served as the mainly immune cells interact with microglia. Furthermore, we systematically characterized alterations in the myeloid-derived cells across the brain, skull, and peripheral blood mononuclear cells (PBMC). Meanwhile, CUMS disrupted immune cell differentiation by suppressing chromatin openness in global accessibility sequencing analyses, and Krüppel-like factors Klf2 emerged as a master regulator expressed in monocytes and HM2 microglial subtype. Remarkably, microbiota remodeling partially reversed this epigenetic dysregulation, restoring immune cell migration and activation processes. In summary, this study revealed that gut microbiota intervention ameliorates depressive phenotypes by dynamically reprogramming microglia via the "periphery-CNS immune" axis, providing a novel entry for antidepressant strategies targeting neuro-immune interactions.

DOI: https://doi.org/10.1038/s41380-026-03545-z
Mol Psychiatry. 2026 Mar 21.

Comprehensive single-cell transcriptomic atlas of microglia in Alzheimer's disease mouse models.

Ping Liu, Tingfang Sun, Jie Yang, Hongrui Li, Wanwan Min, Xingyu Zhou, Ruihan Xiong, Jing Wu, Yu Huang, Yifan Li, Minghao Yuan, Jianping Zhang, Xunmin Tan, Xiaodong Song, Hongsheng Zhang, Ma-Li Wong, Peng Zheng.

Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a comprehensive Mouse Microglia Atlas (MoMicA) to resolve conserved subtypes, delineate dynamic trajectories, and identify key regulators associated with AD pathology. We integrated ten single-cell and single-nucleus RNA-sequencing datasets from major AD mouse models, yielding 84,764 microglia for harmonized clustering, co-expression network analysis, and pseudotime inference, complemented by immune staining. Across models, AD was characterized by contraction of homeostatic microglia and marked expansion of DAM. MoMicA further delineated refined homeostatic and disease-associated subpopulations, including different homeostatic microglia subclusters and a stepwise progression from homeostatic microglia through activated response and pre-disease-associated states to disease-associated microglia. Network analysis highlighted lipid metabolism and inflammation as dominant AD-related programs and identified Fabp5 as a central hub gene within a DAM-associated lipid module. Multiplex immunofluorescence confirmed that Fabp5 is induced in Clec7a-positive DAM around amyloid plaques in two amyloidosis models. MoMicA therefore provides a valuable resource for dissecting the mechanistic roles of microglia in the onset and progression of AD.

DOI: https://doi.org/10.1038/s41380-026-03529-z
Cancer Res. 2026 Mar 24.

MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and are Clinically Relevant Across Central Nervous System Disorders.

Laura Alvaro-Espinosa, Angel Marquez-Galera, Neibla Priego, Virginia García-Calvo, Maria Perea-García, Carolina Hernandez-Oliver, Diana Retana, Oliva Sanchez, Ana de Pablos-Aragoneses, Pedro García-Gómez, Osvaldo Graña-Castro, Óscar Lapuente-Santana, Laura Serrano-Ron, Fatima Al-Shahrour, Ana Cayuela López, Isabel Peset, Diego Megías, Mihaela Ola, Damir Varešlija, Leonie S Young, Yolanda Martí-Mateos, Jose A Enríquez, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Maria S Soengas, Juergen Bernhagen, Alejandro Antón-Fernández, Jesús Ávila, Miguel A Marchena, Maximiliano Torres, Fernando de Castro, Mar Márquez-Ropero, Amanda Sierra, Jose P Lopez-Atalaya, Renacer Group, Manuel Valiente, Patricia Baena Galán, Cecilia Sobrino, Inmaculada Almenara, Daniel Alba-Olano, Carmen Ortega-Sabater, María-Jesús Artiga, Eva Ortega-Paino, Ana González Piñeiro, Concepción Fiaño Valverde, Adolfo de la Lama Zaragoza, Alejandra Londoño Quiroz, Pedro David Delgado López, Mar Pascual-Llorente, Ángela Díaz-Piqueras, Ángel Amador Arriaga Aragón, Syonghyun Nam-Cha, Cristina Barrena-López, Gerard Plans Ahicart, Begoña Escolano Otín, Isabel Gil Aldea, Juan Delgado-Fernández, Juan M Sepúlveda-Sánchez, Angel Perez-Nuñez, Aurelio Hernández-Laín, Oscar Toldos González, Ricardo Gargini, Denisse Alcivar, José A Fernández Alén, Guillermo Blasco García de Andoain, Santiago Cepeda Chafla, Elena Martínez Zamorano, Manuela Mollejo Villanueva, Maria-Sonsoles Opazo Rodríguez, Ángel Rodriguez de Lope Llorca, María Arbaiza Martínez, Gonzalo M Múzquiz Rueda, Sergi Benavente, Fran Martínez-Ricarte, Santiago Ramón Y Cajal, Marta Sesé Faustino, Laura Fernández Cabré, Javier Hernández-Losa, Elena Martínez-Saez, Lourdes Calero Félix, Kelly Vargas-Osorio.

The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. Here, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon gamma in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand MIF that bound the CD74 receptor and induced its translocation to the nucleus where it activated a NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, while it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease non-canonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4018
Brain Behav Immun. 2026 Mar 24. pii: S0889-1591(26)00303-X. [Epub ahead of print] 106555

The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation.

Sahabuddin Ahmed, Christian Bowers, Jose Munoz-Martin, Sumit Jamwal, Basavaraju G Sanganahalli, Kyle Chen, Lauryn Giuliano, Zoë A MacDowell Kaswan, Fahmeed Hyder, X William Yang, Arie Kaffman.

  Childhood neglect and deprivation are the most common forms of early adversity, yet their biological impact on cognitive development-and how enrichment mitigates these effects-remains poorly understood. Using limited bedding (LB) as a mouse model of deprivation, we previously showed that abnormal microglia-mediated synaptic pruning during the second and third postnatal weeks impairs synaptic connectivity and hippocampal function, particularly in males. However, the molecular basis of this microglial dysfunction is unclear. Here, we demonstrate that LB reduces expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) across multiple mouse strains and that TREM2 deficiency accounts for roughly half of the phagocytic deficit. Overexpressing TREM2 restores microglial phagocytic function and rescues deficits in hippocampal connectivity and fear learning later in life. Brief postnatal enrichment normalizes synaptic pruning in a TREM2-dependent manner and restores contextual fear conditioning in adolescent LB male mice. Together, these findings identify TREM2 activity during early development as a key mediator of the long-term impact of deprivation and enrichment on synaptic connectivity and cognitive function.

Keywords:  Early enrichment; Early life adversity; Limited bedding; Synaptic pruning; TREM2

DOI:  https://doi.org/10.1016/j.bbi.2026.106555
Brain Behav Immun. 2026 Mar 25. pii: S0889-1591(26)00311-9. [Epub ahead of print] 106563

Somatostatin-induced modulation of microglial activity contributes to mitigating Alzheimer's disease pathology.

Hyeji Jung, Gaeun Hyun, Seunghye Kim, Younghyeon Jeon, Kyung Ah Han, Kea Joo Lee, Jaewon Ko, Ji Won Um.

  Somatostatin (SST) is a neuropeptide widely expressed in the central nervous system, known to exert inhibitory effects through activation of G protein-coupled somatostatin receptors (SSTRs). Although its synaptic and network-level functions have been implicated in various neurological disorders, the direct peptidergic actions of SST-particularly on microglia-remain poorly understood. Given that SST levels are reduced in Alzheimer's disease (AD) and microglia predominantly express SSTR2, we hypothesized that SST modulates microglial function both in physiological and AD-related contexts. In this study, we demonstrate that SST treatment enhances phagocytic capacity and suppresses pro-inflammatory cytokine release in cultured microglia. Furthermore, SST overexpression in an AD mouse model reduced microglial density and amyloid-β plaque burden and improved hippocampus-dependent cognitive performance, indicating a protective effect mediated through microglial modulation. Our findings suggest a previously unrecognized role of SST in regulating microglial behavior and highlight the therapeutic potential of targeting the SST-SSTR signaling axis in neuroinflammatory and neurodegenerative diseases.

Keywords:  Alzheimer’sdisease; Microglia; Neuroinflammation; Somatostatin

DOI:  https://doi.org/10.1016/j.bbi.2026.106563
Brain Behav Immun. 2026 Mar 24. pii: S0889-1591(26)00308-9. [Epub ahead of print] 106560

Microglia promote vascular remodeling in a mouse model of chronic stress.

Zachary Hage, Miguel M Madeira, Kimberly Nnah, Dimitris Koliatsis, Alexandros G Kokkosis, Laurel E Schappell, Neil A Nadkarni, Stella E Tsirka.

  Major Depressive Disorder (MDD) is a debilitating mental illness affecting over 350 million people globally. Chronic stress is a major risk factor for MDD and is associated with increased vascular dysfunction and cardiovascular disease. While inflammation is often implicated in these pathologies, the specific interactions between immune cells and the cerebral vasculature in the context of chronic stress remain poorly understood. We employed a chronic social defeat stress (CSDS) model in mice to investigate immune-vascular interactions in the medial prefrontal cortex (mPFC). We also used a subthreshold stress model to assess the temporal sequence of microglial and vascular changes. To explore the role of endothelial signaling, we utilized a CD31 knockout model. Microglial activation, vascular morphology, and immune cell infiltration were assessed using immunohistochemistry and functional assays. Chronic stress induced microglial activation and increased microglia-vessel interactions in the mPFC, which were associated with impaired vascular morphology. These interactions were observed to precede vascular changes in the subthreshold model. Cytokines released by interferon (IFN)γ-stimulated microglia promoted macrophage infiltration into the brain. Deletion of endothelial CD31, a key mediator of transendothelial migration, prevented macrophage recruitment and protected against inflammatory, vascular, and behavioral deficits associated with CSDS. Our findings highlight important immune-vascular interactions in chronic stress, where microglia contribute to cerebrovascular remodeling and facilitate macrophage infiltration via CD31-dependent pathways. These interactions may underlie the pathophysiology of MDD and its vascular comorbidities, offering potential therapeutic targets.

Keywords:  Blood Vessel; CD31; Chronic Stress; Endothelial Cell; Inflammation; Macrophage; Major Depressive Disorder; Microglia; PECAM

DOI:  https://doi.org/10.1016/j.bbi.2026.106560
Brain Behav Immun. 2026 Mar 24. pii: S0889-1591(26)00306-5. [Epub ahead of print] 106558

Microglial PRMT2IP alleviates ischemia-induced brain injury.

Min Zhang, Jiexun Cai, Wenting Su, Qi Zeng, Huawei Zhang, Jiahui Deng, Bing Zhai, He Xiao, Gaizhi Zhu, Ran Gao, Jinming Qiu, Ziqing Bian, Guoming Luan, Renxi Wang.

  Microglia serve as the principal instigators of neuroinflammatory cascades following ischemic stroke. We here demonstrated that PRMT2IP (previously named as 1700017B05Rik in mice and C15orf39 in humans) is essential for modulating microglial activation and functional responses in ischemic stroke. Mendelian randomization (MR) analysis demonstrated a causal relationship between downregulation of human PRMT2IP expression and an elevated risk of ischemic stroke. Mouse PRMT2IP expression was downregulated in ischemic microglia. Critically, PRMT2IP overexpression provided a protective role in reducing cerebral ischemia injury, while PRMT2IP knockout showed significantly worsened outcomes. Mechanistically, PRMT2IP interacts with PRMT2 and inhibits the activation of the NF-κB signaling pathway by PRMT2-IκBα signaling axis, ultimately reducing the expression of inflammatory factors IL-6 and TNFα. In conclusion, our results suggest that microglial PRMT2IP, as a key negative regulator of microglial inflammatory response, alleviates ischemia-induced brain injury. Thus, up-regulation of PRMT2IP expression may provide a therapeutic strategy to attenuate deleterious neuroinflammation post-stroke.

Keywords:  Ischemic stroke; Microglia; Neuroinflammation; PRMT2IP

DOI:  https://doi.org/10.1016/j.bbi.2026.106558
Neuron. 2026 Mar 26. pii: S0896-6273(26)00128-5. [Epub ahead of print]

Microglia-mediated protection against Alzheimer's disease pathology and detrimental effects in white matter revealed by Ptpn6 deletion.

Ainhoa Etxeberria, Seung-Hye Lee, Julia A Kuhn, Marinella Callow, Gloriia Novikova, Jean-Philippe Fortin, Man Kin Choy, Luke Xie, Jose Imperio, Steve Vito, Ming-Chi Tsai, Jaclyn Lock, Lucia Taraborrelli, Simone M Haag, Honglin Chen, Monica Ge, Hai Ngu, Oded Foreman, Kim Stark, Brad A Friedman, Benjamin Haley, David V Hansen, William J Meilandt, Amy Easton, Scott Martin, Aditya Murthy, Mike Costa, Christopher J Bohlen.

  Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased neuritic dystrophy around amyloid plaques in the TauPS2APP model of Alzheimer's disease. However, deletion also dysregulated homeostasis in normal white matter and exacerbated neurodegeneration in disease. Heterozygous deletion revealed a differential gene-dosage sensitivity for beneficial and detrimental effects, exhibiting reduced neuritic damage near plaques without white-matter harm. Single-cell RNA sequencing uncovered multiple disease-associated microglia (DAM)-like transcriptional states, with Lgals3+ microglia emerging alongside neurodegeneration after Ptpn6 deletion. In all, these findings reveal both the protective and latent degenerative potential of microglia held in check by Ptpn6.

Keywords:  Alzheimer’s disease; Ptpn6; SHP-1; galectin-3; genome-wide screen; microglia; neurodegeneration; plaque; single-cell RNA-seq; white matter

DOI:  https://doi.org/10.1016/j.neuron.2026.02.023
Nat Commun. 2026 Mar 25.

Polymersomes preventing brain infiltration of CD177+ neutrophils to mitigate hemorrhagic transformation post-tPA thrombolysis.

Zhenhua Wang, Hua Liu, Zhiyao Xu, Cheng Huang, Xing Guo, Shaobing Zhou.

As an intravenous thrombolytic agent, tissue plasminogen activator (tPA) is limited by hemorrhagic transformation (HT) and a narrow therapeutic time window. Here we develop ROS-triggered polymersomes conjugated with fibrin-targeting CREKA peptide (CP) for tPA encapsulation. CP@tPA achieves efficient thrombosis targeting and enhanced thrombolytic efficacy, however, it has not been able to avert the occurrence of hemorrhage subsequent to thrombolysis. Building from our clinical discovery that stroke patients suffer from tPA-induced HT featured strong expression of CD177, recombinant CD177 protein (rCD177) was loaded into CP polymersomes (CP@rCD177) as nanomedicine and administrated prior to CP@tPA thrombolysis. rCD177 can be released in response to elevated ROS within the obstructed vessels, which binds to endothelial cells through interacting with CD31 and efficiently prevents the migration of CD177+ neutrophils into the brain parenchyma. The reduced CD177+ neutrophils suppress the generation of neutrophil extracellular traps (NETs), thereby dampening the inflammatory activation of microglia and ultimately improving the prognosis of HT. This innovative strategy presents a promising avenue for attenuating hemorrhagic complications post-thrombolysis.

DOI: https://doi.org/10.1038/s41467-026-71076-w
Nat Commun. 2026 Mar 27.

Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination.

Weixing Yan, Yelin Zhao, Hui Li, Li Hong, Qi Jia, Di Zhu, Dong Xiang, Li Du, Lang Hu, Ruixue Bai, Meizhen Xu, Yangyang Tang, Xinzhu Chen, Yiwei Cao, Wenyu Jia, Siyu Wang, Yuting Liu, Jinfeng Ren, Shuai Pan, Yanbiao Shi, Sijia Gao, Fuxing Dong, Jianhong Shi, Jinghua Li, Kuiyang Zheng, Jing Yang, Shuli Zhao, Hui Wang.

Aging accelerates central nervous system remyelination failure and neurodegeneration. Microglia promote remyelination by phagocytosing myelin debris, but this function is impaired by aging-related CD22 upregulation. However, the molecular mechanisms counteracting premature aging-related microglial dysfunction and remyelination impairment remain unclear. Here, we report that Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination by restraining progressive CD22 upregulation. We identified that microglia-enriched Bhlhe41 was negatively autoregulated and inhibited by Aurka loss. Bhlhe41- or Aurka-deficient young mice exhibited aging-like microglial morphology, phagocytic deficits, progressive CD22 upregulation, and remyelination impairment in cuprizone-induced demyelination model. Conversely, ectopic Bhlhe41 expression induced hypertrophic microglia, and counteracted phagocytic deficits and CD22 upregulation in Aurka-deficient microglia. CD22 blockade restored phagocytic function and remyelination in Bhlhe41-deficient mice. Notably, a conserved pattern of CD22 upregulation was observed in human PCDH9high microglia subsets with BHLHE41 downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.

DOI: https://doi.org/10.1038/s41467-026-71014-w
Nat Immunol. 2026 Mar 25.

A transcriptomic microglia taxonomy across mouse and human pathologies.

Chintan Chhatbar, Roman Sankowski, Michael Schulz, Takashi Shimizu, Marius Schwabenland, Ori Staszewski, Christian Scheiwe, Stefan Nessler, Katharina Borst, Anaelle Aurelie Dumas, Ella Trost, Daniel Berchtold, Wesley Brandão, Omar Mossad, Adrià Dalmau Gasull, Maximilian Frosch, Daniel Erny, Martin Diebold, Elena Guffart, Katharina Ternka, Mihaela Guranda, Janaki Manoja Vinnakota, Marina Friesen, Koliane Ouk, Inken Waltl, Michael LaMorte, Timothy R Hammond, Giovanni Di Liberto, Ilena Vincenti, Mario Kreutzfeldt, Ibrahim T Mughrabi, Yousef Al-Abed, Thomas Blank, Melanie Meyer-Luehmann, Yanick J Crow, Nellwyn Hagen, Dimitry Ofengeim, Robert Zeiser, Matthias Kettwig, Jutta Gärtner, Andreas Meisel, Martin Schwemmle, Ulrich Kalinke, Jürgen Beck, Bertram Bengsch, Robert Thimme, Oleg Butovsky, Tamara Seredenina, Richard M Ransohoff, Francisco J Quintana, Katrin Kierdorf, Doron Merkler, Christine Stadelmann, Josef Priller, Marco Prinz.

Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.

DOI: https://doi.org/10.1038/s41590-026-02472-z
Signal Transduct Target Ther. 2026 Mar 25. pii: 109. [Epub ahead of print]11(1):

Oligodendrocyte precursor cells-microglia crosstalk via BMP4 drives microglial neuroprotective response and mitigates Alzheimer's disease.

Soonbong Baek, Jaemyung Jang, Seungeun Yeo, Hyun Jin Jung, Youngshik Choe.

Oligodendrocyte precursor cells (OPCs) rapidly respond to neural injury, becoming activated to preserve myelin homeostasis and interacting with diverse cell types in the central nervous system (CNS). However, the molecular basis of OPC communication with the CNS immune system remains poorly understood. In Alzheimer's disease (AD), microglia respond to amyloid pathology in a neuroprotective manner. Here, we found that Bmp4 produced by late-stage OPCs, termed committed oligodendrocyte precursors (COPs), acts as a critical signal shaping microglial neuroprotective programs in the context of amyloid pathology. OPC-specific genetic ablation of Bmp4 in 5xFAD mice suppressed microglial immune responses and exacerbated amyloid deposition. Single-cell RNA sequencing revealed that Bmp4 deficiency in COPs led to downregulation of disease-associated microglia (DAM) genes in the microglial cluster. Mechanistically, Bmp4-dependent Smad1/5/8 signaling directly regulated Trem2 expression in microglia. Replenishment of Bmp4-expressing COPs in 5xFAD mice enhanced Trem2⁺ DAM acquisition, promoting beneficial barrier formation around Aβ plaques. Similarly, intracerebroventricular (ICV) administration of Sox10 promoter-driven AAV-Bmp4 efficiently ameliorated AD progression. Collectively, these findings uncover an OPC-microglia crosstalk that governs immune surveillance in AD, highlighting COP-targeted enhancement of Bmp4 as a promising avenue for interventions aimed at reinforcing early neuroprotective responses.

DOI: https://doi.org/10.1038/s41392-026-02620-9