bims-microg 2026-06-21 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–06–21
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Disruption of the brain-spleen axis impairs monocyte-microglia communication and accelerates disease progression in a mouse model of amyloidosis.
Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m6A-dependent decay of cytosolic mitochondrial mRNAs.
Expression of GPR34 in microglia remains stable in human Alzheimer's disease.
Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants.
Engineered biomimetic exosomes for small activating RNA delivery: Low-density lipoprotein receptor-related protein-1 targeted blood-brain barrier penetration and dual therapy in intracerebral Hemorrhage.
PARP1 rewires neuroinflammatory and redox metabolism associated with reactive neuroglia in neuropathic pain.
Integrated network toxicology and transcriptomics reveal NF-κB signaling as a key mediator of TDCPP-induced inflammatory responses in human microglia.
Shared transcriptomic signatures in perilesional and contralesional cortex after ischemic stroke.
TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.
Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.
Paraventricular oxytocin neurons attenuate post-ischemic brain injury by suppressing microglia-mediated neuroinflammation.
The microglia-derived protein sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish.
Microglial clonal dynamics and the impact of clonal hematopoiesis in autologously transplanted rhesus macaques.
Multi-tier signaling and chromatin remodeling coordinate microglia inflammatory states and activities associated with demyelination.
Characterization of hematopoietic stem cell-derived microglia-like cells in nonhuman primates.
TLR2-Driven NLRP3 Inflammasome Activation Mediates EV71-Induced Neuropathogenesis in Neonatal Mice.
Unveiling a unique microglial phenotype promoting oxidation in the iBRB: insights from single-cell transcriptomics in the NPDR rat model.
Unveiling the molecular crosstalk between the purinergic P2X7 receptor and cannabinoid subtype 2 receptor in human microglial HMC3 cells: New insights for multitarget therapies in neuroinflammation.
Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.
Multiomics Integration Prioritizes ZFP36L1 as a Candidate Susceptibility Gene Associated With Inflammatory and Angiogenic Pathways in Diabetic Retinopathy.

Nat Commun. 2026 Jun 19.

Disruption of the brain-spleen axis impairs monocyte-microglia communication and accelerates disease progression in a mouse model of amyloidosis.

Tommaso Croese, Miguel A Abellanas, Hodaya Polonsky, Michal Arad, Javier M Peralta Ramos, Yuliya Androsova, Serena Riccitelli, Sedi Medina, Francesca Palmas, Romano Strobel, Giulia Castellani, Denise Kviatcovsky, Sarah Phoebeluc-Colaiuta, Miriam Adam, Sama Murad, Hannah Partney, Daniel Kitsberg, Alexander Dieter, Tomer-Meir Salame, Alexander Brandis, Tevie Mehlman, Oded Singer, Michal Rivlin-Etzion, Simon Wiegert, Yosef Shaul, Oren Kobiler, Ofer Yizhar, Naomi Habib, Michal Schwartz.

Alzheimer's disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis reveals reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in coping with disease, we denervated the splenic nerve at an early presymptomatic stage. This intervention accelerated cognitive decline, impaired splenic hematopoiesis, diminished monocyte recruitment to the brain, disrupted monocyte-microglia signaling networks, and reduced the transition of microglia from a homeostatic to a disease-associated (DAM) state. Conversely, enhancing splenic noradrenergic input increased hematopoiesis, restored monocyte homing to the brain, and delayed cognitive impairment. The protective role of splenic monocytes was independently validated in a retinal cytotoxic injury model, in which splenic denervation impairs post-insult survival of retinal ganglion cells. Together, these findings identify an active brain-spleen circuit in regulating monocyte recruitment, and establish peripheral monocytes as important drivers of microglial state transitions and disease progression.

DOI: https://doi.org/10.1038/s41467-026-74253-z
Sci Adv. 2026 Jun 19. 12(25): eadz0887

Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m6A-dependent decay of cytosolic mitochondrial mRNAs.

Wenqi Pan, Lin Yang, Yao Zhang, Yan Chen, Yuesi Xu, Yifan Li, Yujie Fu, Chunhui Ma, Chunying Liu, Qing Li, Hailong Liu, Hailin Wang, Qi Xu, Wei-Min Tong, Yamei Niu.

Dysregulation of RNA m6A modification has been implicated in Alzheimer's disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m6A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-β (Aβ) deposition. Under physiological conditions, cytosolic m6A-modified mt-Nd4 is recognized and degraded by the m6A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I-MAVS innate immune pathway in neurons. Under Aβ-associated pathological conditions, YTHDF2 expression is markedly down-regulated in neurons, leading to the accumulation of m6A-modified mt-Nd4 in the cytosol. This accumulation triggers RIG-I-MAVS activation and type I interferon (IFN) responses. Neuron-derived IFN-β then amplifies neuroinflammation by activating surrounding microglia through a paracrine mechanism. Furthermore, neuronal Ythdf2 deficiency exacerbates Aβ-associated neuroinflammation and cognitive decline. Together, these findings reveal a previously unrecognized m6A/YTHDF2-dependent regulatory axis that links mitochondrial RNA metabolism to innate immune activation and neuroinflammation in Aβ pathology.

DOI: https://doi.org/10.1126/sciadv.adz0887
Acta Neuropathol. 2026 Jun 15. pii: 66. [Epub ahead of print]151(1):

Expression of GPR34 in microglia remains stable in human Alzheimer's disease.

Sophie Seiffer, Jonas Rotter, Jana Brendler, Albert Ricken, Zoe Detzer, Max Braune, Torsten Schöneberg, Angela Schulz, Karsten Winter, Ingo Bechmann.

  Microglia are the resident immune cells of the human central nervous system and play key roles in development, homeostasis, and disease. These functions are mediated by a broad repertoire of cell-surface receptors, including G protein-coupled receptors such as the ADP receptor P2Y12 and GPR34, a receptor for lysophosphatidylserine. While GPR34 deficiency has been linked to impaired microglial phagocytosis, its regulation in relation to amyloid-β (Aβ) and tau pathology in Alzheimer's disease (AD) remains unclear. We performed a quantitative analysis of microglial density, morphology, and GPR34 expression in the medial temporal lobe cortex (MTLC) of elderly human body and tissue donors across the AD spectrum. Using fluorescence in situ hybridization and immunolabeling, we analyzed 187,670 microglial cells and correlated microglial parameters with the severity and spatial proximity of Aβ plaques and tau inclusions. In parallel, we analyzed human single-nucleus RNA sequencing data from 236,002 cells to assess GPR34 expression across microglial subtypes, brain regions, and neuropathological stages. Microglial density and overall morphology in the MTLC were largely preserved, independent of local Aβ or hyperphosphorylated tau burdens. Apart from a moderate shortening of microglial processes in the immediate vicinity of Aβ plaques, no consistent pathology-associated morphological changes were detected. GPR34 expression showed pronounced cell-to-cell variability and differed across microglial subtypes and brain regions, but neither expression intensity nor the proportion of GPR34-positive microglia correlated consistently with Braak stage or Thal phase. These findings suggest that GPR34 regulation in human microglia is highly context-dependent and shaped by regional and cellular heterogeneity rather than AD-associated pathology alone.

Keywords:  Amyloid beta plaques; Glia; Neurodegenerative disease; Neurofibrillary tangles; Neuropathology

DOI:  https://doi.org/10.1007/s00401-026-03035-0
Acta Neuropathol. 2026 Jun 15. pii: 67. [Epub ahead of print]151(1):

Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants.

Nurun N Fancy, Nanet Willumsen, Vicky M N Chau, Samuel L Boulger, Harry J Whitwell, Wenhao Wang, Baptiste Avot, Michael Thomas, Jonathan Talbot-Martin, Stergios Tsartsalis, Combiz Khozoie, Aisling McGarry, Eleonore Schneegans, Riad Yagoubi, To Ka Dorcas Cheung, Marianna Papageorgopoulou, Emily Adair, Benjamin Cooper, Karen Davey, Amy M Smith, William Scotton, John Hardy, Paul M Matthews, Johanna S Jackson.

  TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer's disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865444 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by relative normalisation of differences in β-amyloid load in TREM2var carriers of the protective CD33 allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H compared to CV, and there was a reduction in expression of neuroplasticity pathways in TREM2var. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with phagocytosis and from CV by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var, which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between CV and TREM2var and between the TREM2var risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 inhibition or expression.

Keywords:   CD33 ; TREM2 ; Alzheimer’s disease; Microglia; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1007/s00401-026-03036-z
J Control Release. 2026 Jun 18. pii: S0168-3659(26)00515-8. [Epub ahead of print]396 115112

Engineered biomimetic exosomes for small activating RNA delivery: Low-density lipoprotein receptor-related protein-1 targeted blood-brain barrier penetration and dual therapy in intracerebral Hemorrhage.

Lixing Xu, Yan Song, Huimin Tao, Luyun Ni, Haiqin Huang, Jiabing Shen.

  Efficient brain-targeted gene delivery remains a formidable primary bottleneck in the clinical management of intracerebral hemorrhage (ICH). Herein, we engineered a dual-functional biomimetic nanoplatform (L57-NExos@saRNA) that synergizes active blood-brain barrier (BBB) penetration with intrinsic neuroregeneration. Guided by transcriptomic profiling, a small activating RNA (saRNA) was designed to upregulate activating transcription factor 3 (ATF3) -a critical repressor of the Toll-like receptor 4 (TLR4) neuroinflammatory cascade. To overcome formidable physiological barriers, the saRNA was condensed within neural stem cell-derived exosomes (NExos) surface-functionalized with the low-density lipoprotein receptor-related protein-1 (LRP1)-targeting peptide L57. By proactively exploiting the pathological upregulation of LRP1 on BBB-associated astrocytes following ICH, this L57-modified nanoplatform achieves highly efficient receptor-mediated transcytosis, ensuring robust and specific accumulation at the hemorrhagic lesion. Once internalized, the nanomedicine orchestrates a profound dual-therapeutic response. First, the delivered saRNA specifically reprograms microglia from a neurotoxic (M1) to a neuroprotective (M2) phenotype. This shift fundamentally rectifies maladaptive microglial-astrocyte crosstalk, subsequently driving reactive astrocytes toward an A2 protective state to deeply detoxify the inflammatory microenvironment. Concurrently, the bioactive NExos carrier itself transcends its role as a mere vehicle by activating the PI3K/Akt survival pathway, directly inhibiting neuronal apoptosis and facilitating network repair. By seamlessly converging precise BBB-targeted gene regulation with biomimetic carrier-driven repair, this versatile delivery system presents a highly translational and promising therapeutic paradigm for ICH.

Keywords:  Brain-targeting; LRP1; NExos; Transcytosis; saRNA

DOI:  https://doi.org/10.1016/j.jconrel.2026.115112
Redox Biol. 2026 Jun 18. pii: S2213-2317(26)00267-3. [Epub ahead of print]95 104268

PARP1 rewires neuroinflammatory and redox metabolism associated with reactive neuroglia in neuropathic pain.

Simona Denaro, Simona D'Aprile, Anna Gervasi, Vincenzo Russo, Francesco Bellia, Sebastiano Giallongo, Alessandro Lavoro, Saverio Candido, Alice Braga, Alexander V Gourine, Giovanni Li Volti, Lorella Pasquinucci, Angela Maria Amorini, Carmela Parenti, Rosalba Parenti, Nunzio Vicario.

  Neuroinflammation, oxidative stress and metabolic dysfunction are co-dependent drivers of neuropathic pain, jointly sustaining reactive gliosis and spinal sensitization. The interplay among neuroinflammation, redox imbalance, and metabolic reprogramming in glial cells represents a crucial process in this context, but the integrative mechanisms involved remain elusive. Poly(ADP-ribose) polymerase 1 (PARP1), a nuclear enzyme activated by genotoxic stress, has emerged as a key regulator of neuroinflammatory-associated diseases. The aim of the present study was to investigate the role of PARP1 in the pathophysiology of neuropathic pain and to evaluate the neuroglia phenotype and metabolism. Using a combination of in vitro glial cell cultures and an in vivo model of peripheral nerve injury, we demonstrated that sustained PARP1 activation triggers parthanatos, apoptosis signalling, and reactive gliosis, promoting neuroinflammation and maladaptive redox-inflammatory coupling in the spinal cord. At the behavioural level, PARP1 inhibition attenuated mechanical allodynia and improved motor coordination in rats with chronic constriction injury (CCI) of the sciatic nerve. Multi-omics profiling revealed a broad restoration of injury-altered proteomic and metabolic signatures, converging on restoring redox imbalance and related metabolic pathways, including glutathione and amino acid metabolic processing. Cell-type-specific knockdown of PARP1 established a causal link between redox balance, mitochondrial metabolism, and intercellular crosstalk during microglia inflammatory priming. Taken together, these findings highlight PARP1 as a functional regulator of the glial cell reactive phenotype in neuropathic pain and support its inhibition as a strategy to modulate central sensitization mechanisms.

Keywords:  Central sensitization; Glutathione; Olaparib; PAR polymers; Reactive gliosis

DOI:  https://doi.org/10.1016/j.redox.2026.104268
Environ Int. 2026 Jun 15. pii: S0160-4120(26)00331-4. [Epub ahead of print]214 110373

Integrated network toxicology and transcriptomics reveal NF-κB signaling as a key mediator of TDCPP-induced inflammatory responses in human microglia.

Chuyan Zhang, Tao Song, Jialin Zhou, Xinran Wang, Xia Rao, Chan Ding, Haitao Cao, Zhaoqiang Jiang, Yongxin Li, Huadong Xu, Jianlin Lou.

  Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a ubiquitous organophosphorus flame retardant linked to neurodevelopmental disorders. However, the molecular cascades driving its neurotoxicity, particularly microglial-mediated neuroinflammation, remain incompletely understood. Here, we applied an integrated systems toxicology strategy combining network toxicology, transcriptomics, and experimental validation to identify key pathways mediating TDCPP-induced neurotoxicity. Initial in silico screening of 14 organophosphorus flame retardants (OPFRs) identified TDCPP as a high-priority candidate with prominent predicted neurotoxicity. Integration of network-predicted pathways with transcriptomic profiles from TDCPP-exposed human microglia (HMC3) identified the NF-κB signaling pathway as a key mediator. Experimental validation confirmed that TDCPP activated the canonical NF-κB pathway, characterized by p65 phosphorylation, IκBα degradation, p65 nuclear translocation, and NFKB1 upregulation. This triggered the transcription of pro-inflammatory mediators (IL6, IL1B, TNF, PTGS2) and a secretome shift involving cytokine surges and compensatory IL-10 release. Pharmacological blockade using BAY 11-7082 and siRNA-mediated knockdown of p65 effectively reversed these pro-inflammatory alterations, establishing a causal link. Collectively, this study demonstrates that TDCPP disrupts microglial homeostasis by hijacking the NF-κB signaling axis. These findings indicate that TDCPP alters microglial immune homeostasis and triggers inflammatory responses, which may serve as a mechanistic link to OPFR-associated neurotoxicity, providing a potential target for mitigation.

Keywords:  HMC3 cells; NF-κB signaling pathway; Network toxicology; Neuroinflammation; Neurotoxicity; Organophosphorus flame retardants; TDCPP

DOI:  https://doi.org/10.1016/j.envint.2026.110373
J Neuroinflammation. 2026 Jun 15.

Shared transcriptomic signatures in perilesional and contralesional cortex after ischemic stroke.

Dene Betz, Victoria A Alers, Matthew Kenwood, Kielen R Zuurbier, Rebeca Coimbra, Priscilla Rhoton, Erik J Plautz, Peter M Douglas, Denise M O Ramirez, Ann M Stowe, Mark P Goldberg.

  Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Experimental models have identified repair-associated processes in both the ipsilesional and contralesional cortex, indicating that stroke recovery involves regions both remote and near the lesion. However, most transcriptional studies have focused on the infarct core and peri-lesional cortex (PLC), leaving it unclear whether comparable molecular responses occur in the contralesional cortex (CLC), a region that undergoes substantial remodeling in the absence of direct tissue injury, necrosis, or widespread cellular infiltration. In addition, potential sex-dependent differences in these responses remain incompletely defined, despite known influences of biological sex on post-stroke inflammation and vascular remodeling. To address these gaps, we performed bulk RNA-sequencing of the PLC and CLC at 7 days after photothrombotic stroke, a subacute time point associated with the initiation of repair, in male and female mice. Despite distinct positions relative to the lesion, both regions exhibited robust upregulation of inflammatory signaling, including cytokine-, astrocyte-, and myeloid-lineage-associated pathways. The CLC did not demonstrate a distinct region-specific transcriptional profile; instead, shared signatures between PLC and CLC included genes strongly associated with reactive microglial phenotypes. This shared neuroinflammatory response was largely conserved across sexes. Consistent with these findings, male and female mice exhibited comparable corticospinal tract axonal sprouting originating from the CLC at 6 weeks post-stroke. Together, these findings support a shared neuroinflammatory transcriptional response as a prominent early feature of cortical regions associated with post-stroke plasticity.

Keywords:  Axonal sprouting; Contralesional cortex; Microglia; Perilesional cortex; Post-stroke plasticity; Sex-differences in stroke; Stroke; Stroke recovery

DOI:  https://doi.org/10.1186/s12974-026-03885-1
J Neuroinflammation. 2026 Jun 13.

TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.

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

  Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.

Keywords:  Gasdermin D; Inflammasome Activation; Myeloid Cells; Myeloid Pyroptosis; Photoreceptors; Retinal Degeneration; TREM2

DOI:  https://doi.org/10.1186/s12974-026-03903-2
J Neuroinflammation. 2026 Jun 17.

Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.

Jing Yin, Yan Li, Yu-Lu Miao, Xue-Fang Song, Yao Cheng, Yu-Jie Zhai, Jia Ren, Cai-Hong Yang, Hui-Feng Zhang, Xiang-Nan Zhang, Li-Jun Yang, Yan-Ying Fan.

  Lipid droplet (LD) accumulation in microglia results in a dysfunctional and proinflammatory state after ischemic stroke and worsens neurological outcomes; yet how this accumulation is regulated remains unclear. Interferon regulatory factor 7 (IRF7) is an immune regulatory factor whose role in lipid metabolism and autophagy has been increasingly studied in peripheral tissues. However, the role of IRF7 in microglial lipophagy (a selective autophagic process that targets LDs) and poststroke functional recovery remains unexplored. In this study, using a mouse photothrombotic ischemia (PTI) model, we observed that microglia in the peri-infarct region displayed persistent lipophagy impairment and LD accumulation for up to 21 days. Reanalysis of the single-cell RNA sequencing (scRNA-seq) dataset revealed that an Irf7high microglial MG1 subcluster (disease-associated microglia) was significantly associated with autophagy and lipid metabolism poststroke. Furthermore, microglial Irf7 conditional knockout (Irf7 cKO) mice exhibited a significant rescue of lipophagy impairment and an alleviation of the ensuing LD accumulation in microglia, accompanied by enhanced synaptic plasticity and motor functional recovery during the subacute phase poststroke. Consistently, in the 15-month-old distal middle cerebral artery occlusion (dMCAO) model, Irf7 cKO mice also displayed similar improvements. Similar results were also observed in vitro. Mechanistically, Gnai2 was identified as a positively regulated transcriptional target of IRF7. In BV2 cells and primary microglia, Gnai2 knockdown mitigated lipopolysaccharide (LPS)-induced lipophagy impairment, thereby reducing LD accumulation. This treatment also increased the level of phosphatidylcholine (PC), a key lipid for stabilizing small LDs as well as promoting autophagosome formation and autophagic flux. Consistently, microglial Irf7 deletion or knockdown attenuated stroke- or LPS-induced PC reduction both in vivo and in vitro. Furthermore, exogenous supplementation with CDP-choline, an intermediate in PC synthesis, alleviated LD accumulation and lipophagy impairment, thereby improving motor function. Additionally, delayed administration of an inhibitor of stimulator of interferon genes (STING, an upstream target of IRF7) replicated the beneficial effects observed in Irf7 cKO mice, and its effects were not further enhanced by microglial Irf7 deletion. Taken together, these novel findings reveal that persistent impairment of microglial lipophagy is a key contributor to poststroke LD accumulation, and that IRF7 is involved in this process through direct transcriptional activation of Gnai2, which reduces the PC levels. Suppressing IRF7 with a STING inhibitor is a potential strategy for modulating microglial lipid metabolism and promoting functional recovery following stroke.

Keywords:  IRF7; Lipid droplet; Lipophagy impairment; Microglia; STING; Stroke

DOI:  https://doi.org/10.1186/s12974-026-03902-3
Cell Commun Signal. 2026 Jun 17.

Paraventricular oxytocin neurons attenuate post-ischemic brain injury by suppressing microglia-mediated neuroinflammation.

Rui Liu, Xinyu Yang, Haozhi Gong, Huijie Fang, Xuebing Feng, Jiayao Li, Wentao Gao, Xiaoting Liang, Yanping Shen, Yubo Wang, Wei Wang, Jiaqi Jin, Liqun Jiao.

   BACKGROUND: Neuroinflammation is caused by the overactivation of microglia, contributing to secondary brain injury in ischemic stroke. Oxytocin (OXT), a neuropeptide synthesized by neurons in the paraventricular nucleus (PVN) of the hypothalamus, has demonstrated potential in mitigating inflammatory responses across various pathological conditions. However, research on the role of PVNOXT neurons in ischemic stroke is limited, and the modulatory effect of these neurons on neuroinflammation remains unclear.
METHODS: Transient middle cerebral artery occlusion (tMCAO) was performed in mice. OXT levels were measured in the peri-infarct cortex, serum, and cerebrospinal fluid (CSF), and OXTR expression was assessed in the peri-infarct cortex after tMCAO. Chemogenetic approaches were used to selectively activate PVNOXT neurons in OXT-Cre mice, after which neurological function, infarct volume, and blood-brain barrier integrity were evaluated. To investigate the mechanisms underlying the regulation of ischemic injury by PVNOXT neurons, RNA sequencing of the ipsilateral ischemic hemisphere was performed. Additional analyses, including flow cytometry, molecular assays, and Transwell migration experiments, were conducted to validate the downstream signaling pathways and cellular responses.
RESULTS: OXT levels significantly reduced in the peri-infarct cortex, serum, and CSF, whereas OXTR expression increased in the peri-infarct cortex after tMCAO. Chemogenetic activation of PVNOXT neurons increased OXT levels in both the brain and circulation, reduced infarct volume, and improved neurological outcomes. In addition, transcriptomic analysis identified CXCL3 as one of the most significantly downregulated chemokines after the activation of PVNOXT neurons, and CXCL3 downregulation was associated with reduced neutrophil chemotaxis. Further in vivo and in vitro investigations demonstrated that PVNOXT neurons inhibit microglial CXCL3 expression via the OXTR-ERK signaling pathway, thereby restricting the infiltration of neutrophils. In contrast, the administration of recombinant CXCL3 promoted the recruitment of neutrophils and exacerbated ischemic injury.
CONCLUSIONS: PVNOXT neurons alleviate post-ischemic brain injury by inhibiting the secretion of CXCL3 from microglia, consequently reducing neutrophil chemotaxis. These results underscore the therapeutic potential of targeting PVNOXT neurons and their downstream signaling pathways to mitigate immune-mediated damage in ischemic stroke.

Keywords:  Ischemic stroke; Microglia; Neutrophil chemotaxis; Oxytocin; Paraventricular nucleus

DOI:  https://doi.org/10.1186/s12964-026-03007-7
PLoS Biol. 2026 Jun 18. 24(6): e3003865

The microglia-derived protein sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish.

Alberto Docampo-Seara, Mehmet Ilyas Cosacak, Kim Heilemann, Friederike Kessel, Ana-Maria Oprişoreanu, Markus Westphal, Özge Çark, Daniela Zöller, Josi Arnold, Anja Bretschneider, Alisa Hnatiuk, Nikolay Ninov, Catherina G Becker, Thomas Becker.

Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3, which strongly promotes regenerative neurogenesis. Hence, we propose that sema4ab expression in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signaling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes.

DOI: https://doi.org/10.1371/journal.pbio.3003865
Cell Rep. 2026 Jun 19. pii: S2211-1247(26)00639-X. [Epub ahead of print]45(7): 117561

Microglial clonal dynamics and the impact of clonal hematopoiesis in autologously transplanted rhesus macaques.

Yifan Zhou, Diana M Abraham, Rohan V Hosuru, Taha Bartu Hayal, Ashley L Gin, Xing Fan, Byung-Chul Lee, Taehoon Shin, E Lake Potter, So Gun Hong, Mario Roederer, George S Vassiliou, Chuanfeng Wu, Cynthia E Dunbar.

  Microglia are central nervous system (CNS)-resident macrophages, with key roles in immune surveillance, phagocytosis, and synaptic pruning. Yolk sac-derived microglia show minimal turnover from hematopoietic stem/progenitor cells (HSPCs) under steady-state conditions in mice. However, clinical benefits observed in patients receiving HSPC gene therapies for CNS disorders suggest functional integration of HSPC-derived cells. To investigate microglia replacement and the impact of clonal hematopoiesis (CH) on microglia, we analyzed microglia in rhesus macaques receiving barcoded or CRISPR-edited (TET2-mutant) HSPC transplants. We found that <2% microglia were derived from HSPCs many years following transplant, with no evidence of enhanced replacement in CH. The rare HSPC-derived tissue-resident cells exhibited a macrophage-like gene expression profile. Our results demonstrate limited long-term microglia replacement from adult HSPCs, even with CH, contrasting prior human studies. This work provides insights into microglia ontogeny and informs strategies for CNS-targeted HSPC gene therapies and interpretation of CH-related neuroprotection.

Keywords:  CP: neuroscience; CP: stem cell research; clonal hematopoiesis; hematopoietic stem cell transplantation; microglia; rhesus macaques

DOI:  https://doi.org/10.1016/j.celrep.2026.117561
Cell Rep. 2026 Jun 18. pii: S2211-1247(26)00647-9. [Epub ahead of print]45(7): 117569

Multi-tier signaling and chromatin remodeling coordinate microglia inflammatory states and activities associated with demyelination.

Félix Distéfano-Gagné, Nesrine Belhamiti, William Saxon, Sara Bitarafan, André Machado Xavier, Stéphanie Fiola, Serge Rivest, David Gosselin.

  Complex molecular mechanisms underlie the heterogeneity of microglia immune functions in neurodegenerative diseases. Here, we report on the transcriptional mechanisms that control microglial activities associated with demyelination in mice. Using flow cytometry, microscopy, and RNA-seq, we identify two dominant states of inflammatory microglia: Clec7a+CD229+CD11c- microglia, which are prone to proliferation and express high mRNA levels of Fn1 and Vegfa, and Clec7a+CD229+CD11c+ microglia, which are characterized by prominent mRNA expression of tissue-remodeling and antigen presentation effectors. Achieving these states implicates genome-wide nucleosome remodeling, which is driven by state-dependent stimulation of transcription factors such as Pu.1, AP-1, C/ebp, Mef2, and Egr2. Notably, an H3K27me3-based gatekeeping mechanism controls expression of key regulators, including Egr2. Mechanistically, we validate the relevance of Trem2, Mef2a, and Egr2 to the inflammatory microglial polarization process. Therefore, distinct configurations of signals, along with chromatin remodeling, orchestrate transcription in microglia to support their immune activities in the context of demyelination.

Keywords:  CP: neuroscience; Egr2; H3K27me3; Mef2; Trem2; demyelination; disease-associated microglia; epigenetics; microglia; multiple sclerosis; neuroinflammation

DOI:  https://doi.org/10.1016/j.celrep.2026.117569
Blood Adv. 2026 Jun 18. pii: bloodadvances.2025019337. [Epub ahead of print]

Characterization of hematopoietic stem cell-derived microglia-like cells in nonhuman primates.

Nicholas E Petty, Carl B Wolf, Greta Kanestrom, Mark Mendoza, Kyle Swing, Robert D Murnane, Alvin Tong, Marlena Starrs, Emily Fields, Ravishankar Madhu, Veronica Nelson, Frederick C Bennett, Scott N Furlan, Keith R Loeb, Stefan Radtke, Hans-Peter Kiem.

Hematopoietic stem cell transplantation (HSCT) is the current standard of care for a number of neurotrophic lysosomal storage disorders. The therapeutic mechanism of HSCT is believed to be mediated by engraftment of HSC progeny to the brain as microglia-like cells (MLCs). However, the engraftment of MLCs and their transcriptomic identity relative to endogenous microglia is poorly understood. Here, we utilize the autologous nonhuman primate (NHP) HSCT model to investigate the engraftment of MLCs after gene-modified autologous HSCT. We observed engraftment of gene-marked MLCs across a cohort of five NHPs. MLCs engrafted through diverse brain regions; adopted a homeostatic, ramified morphology, and upregulated core microglial transcripts. We then utilized single cell RNA sequencing to more rigorously evaluate the transcriptome of MLCs, revealing a border-associated macrophage-like phenotype. Our findings offer critical insights into the engraftment and behavior of MLCs post-HSCT, laying the groundwork for their future utilization as a directed therapeutic.

DOI: https://doi.org/10.1182/bloodadvances.2025019337
J Med Virol. 2026 Jun;98(6): e71015

TLR2-Driven NLRP3 Inflammasome Activation Mediates EV71-Induced Neuropathogenesis in Neonatal Mice.

Yingyu Li, Tianrun Liu, Yao Li, Xiaomeng Zhang, Junfei Dai, Jialin Zhang, Baixin Wang, Lei Liu, Rui Wu.

  EV71 is a leading cause of HFMD-associated neurological complications, yet its CNS pathogenic mechanisms remain unclear. Using neonatal BALB/c mice, we identified 10 days post-infection (dpi) as the disease peak, characterized by neuronal necrosis and robust NLRP3 inflammasome activation. We demonstrate that EV71 upregulates TLR2, triggering the NF-κB pathway to prime and activate the NLRP3 inflammasome within microglia. This process drives pro-inflammatory cytokine release and neuroinflammatory damage. Pharmacological blockade of TLR2 with C29 suppressed NF-κB phosphorylation and NLRP3 assembly, reducing viral accumulation by improving the neuroinflammatory microenvironment rather than through direct antiviral activity. Furthermore, the NLRP3 inhibitor MCC950 significantly attenuated clinical symptoms, reduced neuronal apoptosis, and improved survival rates. In summary, our findings identify the TLR2-NF-κB-NLRP3 signaling axis as a central driver of EV71-induced neuroinflammation. This cascade represents a promising host-directed therapeutic target for mitigating the neurological sequelae associated with EV71 infection.

Keywords:  EV71; NLRP3; TLR2; hand, foot, and mouth disease; neural infection

DOI:  https://doi.org/10.1002/jmv.71015
Cell Biosci. 2026 Jun 19.

Unveiling a unique microglial phenotype promoting oxidation in the iBRB: insights from single-cell transcriptomics in the NPDR rat model.

Yifei Geng, Yunqi Zhang, Xiaoyu Xu, Yixin Wang, Yun Luo, Xiaobo Sun.

   BACKGROUND: Early diagnosis and targeted treatment of inner blood-retinal barrier (iBRB) impairment in non-proliferative diabetic retinopathy (NPDR) present significant challenges. This study investigates the cellular heterogeneity and early lesions in the iBRB microenvironment.
METHODS: We created a single-cell transcriptional atlas of NPDR using retinas from Zucker Diabetic Fatty rats, focusing on the expression of cells within the iBRB microenvironment, particularly microglia. We performed cell-cell gene interaction analyses to investigate intercellular communications among different cell types in the iBRB. Additionally, we conducted differentiation potential and trajectory analysis, transcription factor regulatory network characterization, and enrichment analysis of microglia. We also employed transmission electron microscopy, immunofluorescence, and histological analysis to validate the hypothesis.
RESULTS: Based on retinal samples from NPDR rats which had retinal edema and kidney damage, and normal rats, we selected 36,821 cells for subsequent analysis using single-cell sequencing. We identified 669 cells in iBRB and microglia had the highest connectivity value by enrichment analysis. 980 differentially expressed genes related to microglia divide it into 4 subtypes. Among them, Spp1 highly expressed microglia subtype 2 had the highest differentiation potential and was significantly upregulated after NPDR lesions. By integrating histological and biochemical analysis results, the roles of the subtype in the differentiation of microglia in the iBRB microenvironment, such as oxidative stress and apoptosis, were well validated.
CONCLUSION: This study identified a novel microglia type in NPDR rats, offering valuable insight into targeted therapeutic strategies for NPDR patients and enhancing our understanding of microglial regulation within the iBRB.

Keywords:  Inner blood-retina barrier; Microglia; Non-proliferative diabetic retinopathy; Oxidation; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s13578-026-01613-z
Biomed Pharmacother. 2026 Jun 17. pii: S0753-3322(26)00682-7. [Epub ahead of print]201 119646

Unveiling the molecular crosstalk between the purinergic P2X7 receptor and cannabinoid subtype 2 receptor in human microglial HMC3 cells: New insights for multitarget therapies in neuroinflammation.

Imane Ghafir El Idrissi, David Moreira Alvarez, Rocío Piña Márquez, Elena Adinolfi, Anna Pegoraro, Rosaria Volpini, Michela Buccioni, Beatrice Francucci, Ciro Leonardo Pierri, Carmen Abate, Marcello Leopoldo, Josè Brea, Marialessandra Contino, Maria Isabel Loza, Enza Lacivita.

   BACKGROUND: Microglia-mediated neuroinflammation plays a pivotal role in the progression and possible onset of numerous neurodegenerative diseases. A promising therapeutic approach involves shifting microglial polarization from a pro-inflammatory to an anti-inflammatory phenotype. Two receptors central to this process are the purinergic P2X7 receptor, an ATP-gated ion channel that promotes pro-inflammatory signaling, and the cannabinoid receptor subtype 2, a Gi/o protein-coupled receptor associated with anti-inflammatory effects.
METHODS: Here, we investigated the therapeutic potential of pharmacological modulation of these receptors in human HMC3 microglial cells stimulated with LPS, IFNγ, and BzATP. Specifically, we evaluated three selective P2X7R antagonists (A740003, JNJ-54173717, and GI-39) in combination with the CB2R agonist GW405833. Functional outcomes were assessed by measuring intracellular calcium accumulation, plasma membrane permeabilization, and cytokine release.
RESULTS: Co-treatment with P2X7R antagonists and GW405833 markedly attenuated intracellular calcium accumulation, membrane permeabilization, and IL-6 secretion, while enhancing IL-4 release. When CP55,940, a non-selective cannabinoid receptor agonist, was used in combination with P2X7R antagonists, the pharmacological activity of the selective CB2R agonist was substantially reduced. This suggests that the observed effects result from a combined interaction between CB2R activation and P2X7R inhibition rather than from alternative mechanisms. Docking analyses were used as a qualitative tool to explore possible ligand accommodation within P2X7R and CB2R binding pockets.
CONCLUSIONS: Concurrent modulation of P2X7R and CB2R produces enhanced anti-inflammatory effects in activated HMC3 cells. This multitarget strategy offers a promising therapeutic avenue for controlling neuroinflammation and for the development of improved interventions for neurodegenerative disorders.

Keywords:  CB2 Receptor; Human Microglial Cells; Multitarget Therapy; Neurodegeneration; Neuroinflammation; P2X7 Receptor; Pro- and Anti-Inflammatory agents

DOI:  https://doi.org/10.1016/j.biopha.2026.119646
Sci Rep. 2026 06 15. pii: 18516. [Epub ahead of print]16(1):

Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.

Gamze Özata, Rachel M Wise, Aida Cardona-Alberich, Naiyareen F Mayeen, Stephan A Müller, Stefan F Lichtenthaler, Luigi Zecca, Lena F Burbulla.

Microglia are the brain's resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer's and Parkinson's disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.

DOI: https://doi.org/10.1038/s41598-026-55648-w
J Diabetes Res. 2026 ;2026(1): e4312504

Multiomics Integration Prioritizes ZFP36L1 as a Candidate Susceptibility Gene Associated With Inflammatory and Angiogenic Pathways in Diabetic Retinopathy.

Ruiqing Dong, Xiaoli Hui, Chenwen Luo, Shengnan Chen, Ning Gao, Mingqian He, Bingyin Shi, Wei Qiang.

   BACKGROUND: Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and a leading cause of blindness despite available therapies, underscoring the need for novel therapeutic targets.
METHODS: Integrated multiomics analysis combining (1) exploratory single-cell RNA sequencing of rat retinal tissues (three DRs vs. two controls), (2) Mendelian randomization (MR) using whole-blood eQTL data and DR GWAS data (14,584 cases vs. 202,082 controls), and (3) supportive RT-qPCR validation in peripheral-blood clinical samples (30 DRs vs. 30 controls).
RESULTS: (1) Genetic causality was as follows: MR analysis demonstrated ZFP36L1 as a novel DR risk gene (OR = 1.156, 95% CI = 1.054-1.269, p = 0.002), with significant upregulation in patient blood samples (p < 0.0001). (2) Inflammatory regulation was as follows: ZFP36L1 showed strong correlations with proinflammatory markers (TNF-α and IL-6) and immune cell infiltration (parainflammation and Tregs), while negatively correlating with B cells. (3) Pathway mechanisms were as follows: Functional enrichment analyses suggested potential links between ZFP36L1 and NF-κB-related inflammatory signaling as well as TGF-β-related angiogenic pathways. Despite its known VEGF mRNA destabilizing function, we observed a positive ZFP36L1-VEGF correlation (r = 0.180, p < 0.001), an unexpected finding under diabetic conditions.
CONCLUSIONS: ZFP36L1 is a candidate DR susceptibility gene whose genetically regulated expression in blood is associated with DR risk. Retinal single-cell and pathway analyses provide supportive, hypothesis-generating evidence that ZFP36L1 may be linked to inflammatory and angiogenic processes relevant to DR. Further retina-specific and functional studies are required to determine whether ZFP36L1 directly regulates retinal inflammation or angiogenesis in human DR.

Keywords:  Mendelian randomization; NF-κB signaling; ZFP36L1; diabetic retinopathy; inflammation; single-cell RNA sequencing

DOI:  https://doi.org/10.1155/jdr/4312504