bims-microg 2024-10-20 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–10–20
27 papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations.
Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.
In vivo imaging in mouse spinal cord reveals that microglia prevent degeneration of injured axons.
Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline.
Isolation and Whole-Cell Patch-Clamp Recording of Hippocampal Microglia from Adult Mice.
Microglia morphological response to mesenchymal stromal cell extracellular vesicles demonstrates EV therapeutic potential for modulating neuroinflammation.
A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.
A critical role for microglia in regulating metabolic homeostasis and neural repair after spinal cord injury.
Loss of C1q alters the auditory brainstem response.
SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke.
Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer's disease.
The Activation of Muscarinic Acetylcholine Receptors Protects against Neuroinflammation in a Mouse Model through Attenuating Microglial Inflammation.
A novel biomimetic nanovesicle containing caffeic acid-coupled carbon quantum dots for the the treatment of Alzheimer's disease via nasal administration.
Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.
Therapeutic effects of exercise on depression: The role of microglia.
Network dynamics-based subtyping of Alzheimer's disease with microglial genetic risk factors.
Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke.
Prevention and Treatment Strategies for Alzheimer's Disease: Focusing on Microglia and Astrocytes in Neuroinflammation.
RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide.
Minocycline prevents early age-related cognitive decline in a mouse model of intellectual disability caused by ZBTB18/RP58 haploinsufficiency.
Polarized Macrophage functions are affected differentially after CSF-1R Inhibition with PLX5622.
Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein.
Microglia-astrocyte crosstalk is regulated by Astragalus polysaccharides mediated through suppression of Sema4D-PlexinB2 signaling in experimental autoimmune encephalomyelitis.
Transient CSF1R inhibition ameliorates behavioral deficits in Cntnap2 knockout and valproic acid-exposed mouse models of autism.
GSP1-111 Modulates the Microglial M1/M2 Phenotype by Inhibition of Toll-like Receptor 2: A Potential Therapeutic Strategy for Depression.
Proinflammatory microglial activation impairs in vitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor.
MAVS signaling shapes microglia responses to neurotropic virus infection.

Immunity. 2024 Oct 08. pii: S1074-7613(24)00451-5. [Epub ahead of print]

Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations.

James L Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M Tsankova, Maria G Castro, Matthew Schniederjan, Nitin R Wadhwani, G Praveen Raju, Peter Morgenstern, Oren J Becher, Adam L Green, Alexander M Tsankov, Dolores Hambardzumyan.

  Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.

Keywords:  CCR1; CCR5; TAM; diffuse midline glioma; disease-associated macrophage; high-grade glioma; macrophage; microglia; monocyte; pediatric glioma

DOI:  https://doi.org/10.1016/j.immuni.2024.09.007
Immunity. 2024 Oct 09. pii: S1074-7613(24)00458-8. [Epub ahead of print]

Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.

Seiji Kaji, Stefan A Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Martina Schifferer, Michael Willem, Klaus-Armin Nave, Christian Haass, Thomas Arzberger, Sarah Jäkel, Oliver Wirths, Gesine Saher, Mikael Simons.

  The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.

Keywords:  Alzheimer’s disease; ApoE; inflammation; lipids; microglia

DOI:  https://doi.org/10.1016/j.immuni.2024.09.014
Nat Commun. 2024 Oct 13. 15(1): 8837

In vivo imaging in mouse spinal cord reveals that microglia prevent degeneration of injured axons.

Wanjie Wu, Yingzhu He, Yujun Chen, Yiming Fu, Sicong He, Kai Liu, Jianan Y Qu.

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. The contact associated with neuronal activity occurs in a random scanning pattern. In response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This wrapping behavior is dependent on the function of microglial P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) and two-pore-domain potassium (K2P) channels contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of single spinal cord axon injury, achieved through neuron-glia interaction.

DOI: https://doi.org/10.1038/s41467-024-53218-0
Front Immunol. 2024 ;15 1426975

Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline.

Sarah A DeVries, Christina Dimovasili, Maria Medalla, Tara L Moore, Douglas L Rosene.

  Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated in Multiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.

Keywords:  C1q; CD47; complement system; innate immune system; microglia; neurodegeneration; white matter

DOI:  https://doi.org/10.3389/fimmu.2024.1426975
J Vis Exp. 2024 Sep 27.

Isolation and Whole-Cell Patch-Clamp Recording of Hippocampal Microglia from Adult Mice.

Yu Chen, Cheng Long, Li Yang.

Microglia are resident immune cells in the brain that interact with neurons to maintain the homeostasis of the central nervous system (CNS). Studies show that the microglial surface expresses potassium channels that regulate microglial activation, while abnormalities in these potassium channels can lead to neural diseases. Currently, whole-cell patch-clamp recordings of microglia are mostly performed on cultured primary microglia from fetal or newborn mice due to difficulties in conducting electrophysiological evaluations on acutely isolated microglia. This study introduces an easy-to-follow protocol for isolating hippocampal microglia from adult mice and performing whole-cell patch-clamp recordings on the isolated cells. Briefly, the brain was removed from a mouse after decapitation, the hippocampus was dissected bilaterally, and microglia were isolated using an adult mouse brain dissociation kit. The microglia were then purified using a magnetic-activated cell sorting (MACS) method and seeded onto coverslips. Successful microglial isolation was confirmed by immunofluorescent staining with anti-CD11 and anti-Iba1 antibodies. A cover slip was placed in a recording chamber, and the whole-cell potassium currents of the acutely isolated microglia were recorded under voltage-clamp conditions.

DOI: https://doi.org/10.3791/67315
J Biol Eng. 2024 Oct 17. 18(1): 58

Microglia morphological response to mesenchymal stromal cell extracellular vesicles demonstrates EV therapeutic potential for modulating neuroinflammation.

Kanupriya R Daga, Andrew M Larey, Maria G Morfin, Kailin Chen, Sara Bitarafan, Jana M Carpenter, Hannah M Hynds, Kelly M Hines, Levi B Wood, Ross A Marklein.

   BACKGROUND: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation- relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs.
RESULTS: Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-α /IFN-γ stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism.
CONCLUSION: This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphometric approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.

Keywords:  Lipidomics; Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs); Microglia; Mitochondria; Morphology; Morphometry; Neuroinflammation; Proteomics; Secretion

DOI:  https://doi.org/10.1186/s13036-024-00449-w
Nat Neurosci. 2024 Oct 15.

A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.

John F Tuddenham, Mariko Taga, Verena Haage, Victoria S Marshe, Tina Roostaei, Charles White, Annie J Lee, Masashi Fujita, Anthony Khairallah, Ya Zhang, Gilad Green, Bradley Hyman, Matthew Frosch, Sarah Hopp, Thomas G Beach, Geidy E Serrano, John Corboy, Naomi Habib, Hans-Ulrich Klein, Rajesh Kumar Soni, Andrew F Teich, Richard A Hickman, Roy N Alcalay, Neil Shneider, Julie Schneider, Peter A Sims, David A Bennett, Marta Olah, Vilas Menon, Philip L De Jager.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and high-dimensional MERFISH. We also leverage our dataset as a classification resource, finding that induced pluripotent stem cell model systems capture substantial in vivo heterogeneity. Finally, we identify and validate compounds that recapitulate certain subtypes in vitro, including camptothecin, which downregulates the signature of disease-enriched subtypes and upregulates a signature previously associated with Alzheimer's disease.

DOI: https://doi.org/10.1038/s41593-024-01764-7
Free Radic Biol Med. 2024 Oct 14. pii: S0891-5849(24)00990-0. [Epub ahead of print]

A critical role for microglia in regulating metabolic homeostasis and neural repair after spinal cord injury.

Huan Jian, Kailin Wu, Yigang Lv, Jiawei Du, Mengfan Hou, Chi Zhang, Jianqing Gao, Hengxing Zhou, Shiqing Feng.

  Traumatic spinal cord injury (SCI) often results in severe immune and metabolic disorders, aggravating neurological damage and inhibiting locomotor functional recovery. Microglia, as resident immune cells of the spinal cord, play crucial roles in maintaining neural homeostasis under physiological conditions. However, the precise role of microglia in regulating immune and metabolic functions in SCI is still unclear and is easily confused with that of macrophages. In this study, we pharmacologically depleted microglia to explore the role of microglia after SCI. We found that microglia are beneficial for the recovery of locomotor function. Depleting microglia disrupted glial scar formation, reducing neurogenesis and angiogenesis. Using liquid chromatography tandem mass spectrometry (LC‒MS/MS), we discovered that depleting microglia significantly inhibits lipid metabolism processes such as fatty acid degradation, unsaturated fatty acid biosynthesis, glycophospholipid metabolism, and sphingolipid metabolism, accompanied by the accumulation of multiple organic acids. Subsequent studies demonstrated that microglial depletion increased the inhibition of FASN after SCI. FASN inhibition exacerbated malonyl-CoA accumulation and significantly impeded the activity of mTORC1. Moreover, microglial depletion exacerbated the oxidative stress of neurons. In summary, our results indicate that microglia alleviate neural damage and metabolic disorders after SCI, which is beneficial for achieving optimal neuroprotection and neural repair.

Keywords:  Metabolism; Microglia; Oxidative Stress; Spinal cord injury; mTORC1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.288
Front Cell Neurosci. 2024 ;18 1464670

Loss of C1q alters the auditory brainstem response.

Sima M Chokr, Ashley Bui-Tran, Karina S Cramer.

  Neural circuits in the auditory brainstem compute interaural time and intensity differences used to determine the locations of sound sources. These circuits display features that are specialized for these functions. The projection from the ventral cochlear nucleus (VCN) to the medial nucleus of the trapezoid (MNTB) body travels along highly myelinated fibers and terminates in the calyx of Held. This monoinnervating synapse emerges during development as multiple inputs are eliminated. We previously demonstrated that elimination of microglia with a colony stimulating factor-1 inhibitor results in impaired synaptic pruning so that multiple calyceal terminals reside on principal cells of MNTB. This inhibitor also resulted in impaired auditory brainstem responses (ABRs), with elevated thresholds and increased peak latencies. Loss of the microglial fractalkine receptor, CX3CR1, decreased peak latencies in the ABR. The mechanisms underlying these effects are not known. One prominent microglial signaling pathway involved in synaptic pruning and plasticity during development and aging is the C1q-initiated compliment cascade. Here we investigated the classical complement pathway initiator, C1q, in auditory brainstem maturation. We found that C1q expression is detected in the MNTB by the first postnatal week. C1q levels increased with age and were detected within microglia and surrounding the soma of MNTB principal neurons. Loss of C1q did not affect microglia-dependent calyceal pruning. Excitatory and inhibitory synaptic markers in the MNTB and LSO were not altered with C1q deletion. ABRs showed that C1q KO mice had normal hearing thresholds but shortened peak latencies. Altogether this study uncovers the developmental time frame of C1q expression in the sound localization pathway and shows a subtle functional consequence of C1q knockdown.

Keywords:  auditory brainstem; complement; medial nucleus of the trapezoid body (MNTB); microglia; neural development

DOI:  https://doi.org/10.3389/fncel.2024.1464670
Brain Res Bull. 2024 Oct 11. pii: S0361-9230(24)00235-1. [Epub ahead of print]218 111101

SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke.

Jie Zhu, Panshi Jin, Tingting Zhou, Dingshun Zhang, Zixin Wang, Zhen Tang, Zhifeng Liu, Guangli Ren.

   BACKGROUND: Brain injury often results in high mortality rates and significant sequelae following severe heatstroke (HS). Neuroinflammation aggravates HS-induced brain injury, yet the involvement of microglia in heat-induced neuroinflammation deserves further investigation.
METHODS: Our study investigated activation status, phenotype markers, production of pro-inflammatory cytokine and reactive oxygen species (ROS) of microglia both in vitro and in vivo under HS. Utilizing high-throughput sequencing, we identified SIRT1 as a potential modulator of microglia phenotype, and observed that SIRT1 alleviated severe heatstroke-induced brain injury following intraperitoneal administration of the SIRT1 agonist SRT-1720 and the inhibitor selisistat. Additionally, the effects of SRT-1720 and selisistat on mitochondrial dynamics and microglial phenotype transition were examined in BV2 cells in vitro.
RESULTS: Heatstroke promotes microglia activation, as evidenced by the increased production of pro-inflammatory cytokine and reactive oxygen species. High-throughput sequencing revealed elevated expression of SIRT1 in BV2 cells under HS. Upon inhibition of SIRT1 expression, there was a corresponding increase in pro-inflammatory cytokine, iNOS, and ROS expression in BV2 cells. In vivo experiments with the SIRT1 agonist SRT-1720 showed a mitigation of neuron injury under HS, as assessed by Nissl and HE staining. Activation of SIRT1 was associated with a reduction in mitochondrial injury and a decrease in the phosphorylation of mitochondrial fission protein Drp1ser616. Furthermore, the heat-induced activation of microglia was reversed by the Drp1 inhibitor, Mdivi.
CONCLUSIONS: Our findings provided evidence that SIRT1 played a crucial role in inhibiting heat stress-induced microglial activation. By suppressing the phosphorylation of mitochondrial fission protein Drp1, SIRT1 contributed to the reduction of neuroinflammation and severity of heatstroke-induced brain injury.

Keywords:  Heatstroke; Microglia; Mitochondrial quality control; Neuroinflammation; SIRT1

DOI:  https://doi.org/10.1016/j.brainresbull.2024.111101
J Neuroinflammation. 2024 Oct 15. 21(1): 261

Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer's disease.

Zhixin Zhang, Miao Li, Xiang Li, Zhiyang Feng, Gan Luo, Ying Wang, Xiaoyan Gao.

  The NLR family pyrin domain containing 3 (NLRP3) inflammasome in microglia is intimately linked to the pathogenesis of Alzheimer's disease (AD). Although NLRP3 inflammasome activity is regulated by cellular metabolism, the underlying mechanism remains elusive. Here, we found that under the pathological conditions of AD, the activation of NLRP3 inflammasome in microglia is accompanied by increased glutamine metabolism. Suppression of glutaminase, the rate limiting enzyme in glutamine metabolism, attenuated the NLRP3 inflammasome activation both in the microglia of AD mice and cultured inflammatory microglia. Mechanistically, inhibiting glutaminase blocked the anaplerotic flux of glutamine to the tricarboxylic acid cycle and amino acid synthesis, down-regulated mTORC1 signaling by phosphorylating AMPK, which stimulated mitophagy and limited the accumulation of intracellular reactive oxygen species, ultimately prevented the activation of NLRP3 inflammasomes in activated microglia during AD. Taken together, our findings suggest that glutamine metabolism regulates the activation of NLRP3 inflammasome through mitophagy in microglia, thus providing a potential therapeutic target for AD treatment.

Keywords:  Alzheimer’s disease; Glutamine metabolism; Microglia; Mitophagy; NLRP3 inflammasome

DOI:  https://doi.org/10.1186/s12974-024-03254-w
Int J Mol Sci. 2024 Sep 27. pii: 10432. [Epub ahead of print]25(19):

The Activation of Muscarinic Acetylcholine Receptors Protects against Neuroinflammation in a Mouse Model through Attenuating Microglial Inflammation.

Kaichun Wang, Yuanyuan Xie, Xixiang Chen, Xiaoyan Ouyang, Lanxue Zhao, Hongzhuan Chen, Jianrong Xu.

  Neuroinflammation is a critical factor that contributes to neurological impairment and is closely associated with the onset and progression of neurodegenerative diseases. In the central nervous system (CNS), microglia play a pivotal role in the regulation of inflammation through various signaling pathways. Therefore, mitigating microglial inflammation is considered a promising strategy for restraining neuroinflammation. Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the CNS and exhibit clear neuroprotective effects in various disease models. However, whether the activation of mAChRs can harness benefits in neuroinflammation remains largely unexplored. In this study, the anti-inflammatory effects of mAChRs were found in a neuroinflammation mouse model. The expression of various cytokines and chemokines was regulated in the brains and spinal cords after the administration of mAChR agonists. Microglia were the primary target cells through which mAChRs exerted their anti-inflammatory effects. The results showed that the activation of mAChRs decreased the pro-inflammatory phenotypes of microglia, including the expression of inflammatory cytokines, morphological characteristics, and distribution density. Such anti-inflammatory modulation further exerted neuroprotection, which was found to be even more significant by the direct activation of neuronal mAChRs. This study elucidates the dual mechanisms through which mAChRs exert neuroprotective effects in central inflammatory responses, providing evidence for their application in inflammation-related neurological disorders.

Keywords:  microglia; muscarinic acetylcholine receptors; neuroinflammation; neuron

DOI:  https://doi.org/10.3390/ijms251910432
J Nanobiotechnology. 2024 Oct 19. 22(1): 642

A novel biomimetic nanovesicle containing caffeic acid-coupled carbon quantum dots for the the treatment of Alzheimer's disease via nasal administration.

Yu Hu, Jingwen Cui, Junpeng Sun, Xiaobang Liu, Shuang Gao, Xifan Mei, Chao Wu, He Tian.

  Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive cognitive and physical impairment. Neuroinflammation is related to AD, and the misfolding and aggregation of amyloid protein in the brain creates an inflammatory microenvironment. Microglia are the predominant contributors to neuroinflammation, and abnormal activation of microglia induces the release of a large amount of inflammatory factors, promotes neuronal apoptosis, and leads to cognitive impairment. In this study, we used microglial membranes containing caffeic acid-coupled carbon quantum dots to prepare a novel biomimetic nanocapsule (CDs-CA-MGs) for the treatment of AD. The application of CDs-CA-MGs via nasal administration can bypass the blood‒brain barrier (BBB) and directly target the site of inflammation. After treatment with CDs-CA-MGs, AD mice showed reduced inflammation in the brain, decreased neuronal apoptosis, and significantly improved learning and memory abilities. In addition, CDs-CA-MGs affect inflammation-related JAK-STAT and Toll-like receptor signaling pathways in AD mice. CDs-CA-MGs significantly downregulated interleukins (IL-1β and IL-6) and tumor necrosis factor (TNF-α). This finding suggested that CDs-CA-MGs may improve cognitive impairment by modulating inflammatory responses. In conclusion, the use of CDs-CA-MGs provides a possible therapeutic strategy for the treatment of AD.

Keywords:  Alzheimer’s disease; Caffeic acid; Carbon quantum dots; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12951-024-02912-8
J Biol Chem. 2024 Oct 10. pii: S0021-9258(24)02376-7. [Epub ahead of print] 107874

Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.

Da Lin, Sarah Kaye, Min Chen, Amogh Lyanna, Lihua Ye, Luke A Hammond, Jie Gao.

  Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of AppNL-G-F, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology to delineate the impacts of Aβ deposition on brain cells. By contrasting AppNL-G-F mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight altered microglial states as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate altered microglial states and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.

Keywords:  Alzheimer’s disease; Microglia; brain metabolism; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2024.107874
Brain Res. 2024 Oct 13. pii: S0006-8993(24)00533-X. [Epub ahead of print] 149279

Therapeutic effects of exercise on depression: The role of microglia.

Li Li, Li Ren, Bing Li, Chaomeng Liu.

  Major depressive disorderadversely affects mental health. Traditional therapeutic approaches, including medication, psychological intervention, and physical therapy, exert beneficial effects on depression. However, these approaches are associated with some limitations, such as high cost, adverse reactions, recurrent episodes, and low patient adherence. Previous studies have demonstrated that exercise therapy can effectively mitigate depressive symptoms, although the underlying mechanism has not been elucidated. Recent studies have suggested that depression is a microglial disease. Microglia regulate the inflammatory response, synaptic plasticity, neurogenesis, kynurenine pathway and the activation of hypothalamic-pituitary-adrenal axis, all of which affect depression. Exercise therapy is reported to shift the balance of microglial M1/M2 polarization in the hippocampus, frontal lobe, and striatum, suppressing the release of pro-inflammatory factors and consequently alleviating behavioral deficits in animal models of depression. Further studies are needed to examine the specific effects of different exercise regimens on microglia to identify the exercise regimen with the best therapeutic effect.

Keywords:  Exercise; Inflammatory response; Kynurenine pathway; Major depressive disorder; Microglia

DOI:  https://doi.org/10.1016/j.brainres.2024.149279
Alzheimers Res Ther. 2024 Oct 16. 16(1): 229

Network dynamics-based subtyping of Alzheimer's disease with microglial genetic risk factors.

Jae Hyuk Choi, Jonghoon Lee, Uiryong Kang, Hongjun Chang, Kwang-Hyun Cho.

   BACKGROUND: The potential of microglia as a target for Alzheimer's disease (AD) treatment is promising, yet the clinical and pathological diversity within microglia, driven by genetic factors, poses a significant challenge. Subtyping AD is imperative to enable precise and effective treatment strategies. However, existing subtyping methods fail to comprehensively address the intricate complexities of AD pathogenesis, particularly concerning genetic risk factors. To address this gap, we have employed systems biology approaches for AD subtyping and identified potential therapeutic targets.
METHODS: We constructed patient-specific microglial molecular regulatory network models by utilizing existing literature and single-cell RNA sequencing data. The combination of large-scale computer simulations and dynamic network analysis enabled us to subtype AD patients according to their distinct molecular regulatory mechanisms. For each identified subtype, we suggested optimal targets for effective AD treatment.
RESULTS: To investigate heterogeneity in AD and identify potential therapeutic targets, we constructed a microglia molecular regulatory network model. The network model incorporated 20 known risk factors and crucial signaling pathways associated with microglial functionality, such as inflammation, anti-inflammation, phagocytosis, and autophagy. Probabilistic simulations with patient-specific genomic data and subsequent dynamics analysis revealed nine distinct AD subtypes characterized by core feedback mechanisms involving SPI1, CASS4, and MEF2C. Moreover, we identified PICALM, MEF2C, and LAT2 as common therapeutic targets among several subtypes. Furthermore, we clarified the reasons for the previous contradictory experimental results that suggested both the activation and inhibition of AKT or INPP5D could activate AD through dynamic analysis. This highlights the multifaceted nature of microglial network regulation.
CONCLUSIONS: These results offer a means to classify AD patients by their genetic risk factors, clarify inconsistent experimental findings, and advance the development of treatments tailored to individual genotypes for AD.

Keywords:  Alzheimer’s disease; Genetic risk factors; Microglia; Network dynamics; Patient subtyping; Systems biology

DOI:  https://doi.org/10.1186/s13195-024-01583-9
Cell Signal. 2024 Oct 15. pii: S0898-6568(24)00439-X. [Epub ahead of print] 111466

Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke.

Guangming Zhang, Anliu Zhao, Xiaolu Zhang, Miao Zeng, Huayuan Wei, Xu Yan, Jie Wang, Xijuan Jiang, Yongna Dai.

  Ischemic stroke is currently the second leading cause of mortality worldwide, with limited treatment options available. As resident immune cells, microglia promptly respond to cerebral ischemic injury, influencing neuroinflammatory damage and neurorepair. Studies suggest that microglia undergo metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis in response to ischemia, significantly impacting their function during ischemic stroke. Therefore, this study aims to investigate the roles and regulatory mechanisms involved in this process, aiming to identify a new therapeutic target or potential drug candidate.

Keywords:  Glycolysis; Ischemic stroke; Microglia; Neuroinflammation; Polarization

DOI:  https://doi.org/10.1016/j.cellsig.2024.111466
J Inflamm Res. 2024 ;17 7235-7259

Prevention and Treatment Strategies for Alzheimer's Disease: Focusing on Microglia and Astrocytes in Neuroinflammation.

Shenghao Zhang, Zhejianyi Gao, Lina Feng, Mingquan Li.

  Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by its insidious onset and progressive development, making it the most common form of dementia. Despite its prevalence, the exact causes and mechanisms responsible for AD remain unclear. Recent studies have highlighted that inflammation in the central nervous system (CNS) plays a crucial role in both the initiation and progression of AD. Neuroinflammation, an immune response within the CNS triggered by glial cells in response to various stimuli, such as nerve injury, infection, toxins, or autoimmune reactions, has emerged as a significant factor alongside amyloid deposition and neurofibrillary tangles (NFTs) commonly associated with AD. This article aims to provide an overview of the most recent research regarding the involvement of neuroinflammation in AD, with a particular focus on elucidating the specific mechanisms involving microglia and astrocytes. By exploring these intricate processes, a new theoretical framework can be established to further probe the impact of neuroinflammation on the development and progression of AD. Through a deeper understanding of these underlying mechanisms, potential targets for therapeutic interventions and novel treatment strategies can be identified in the ongoing battle against AD.

Keywords:  alzheimer’s disease; astrocyte; microglia; neuroinflammation; review

DOI:  https://doi.org/10.2147/JIR.S483412
bioRxiv. 2024 Oct 12. pii: 2024.10.09.617444. [Epub ahead of print]

RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide.

Changjun Yang, Maria Carolina Machado da Silva, John A Howell, Jonathan Larochelle, Lei Liu, Rachel E Gunraj, Antônio Carlos Pinheiro de Oliveira, Eduardo Candelario-Jalil.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that plays an essential role in the modulation of innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription of Nos2 , Ptgs2 , Il-1β , Tnfα , Il6 , Ccl2 , and Mmp9 . However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS.

DOI: https://doi.org/10.1101/2024.10.09.617444
J Neuroinflammation. 2024 Oct 12. 21(1): 260

Minocycline prevents early age-related cognitive decline in a mouse model of intellectual disability caused by ZBTB18/RP58 haploinsufficiency.

Tomoko Tanaka, Shinobu Hirai, Hiroyuki Manabe, Kentaro Endo, Hiroko Shimbo, Yasumasa Nishito, Junjiro Horiuchi, Hikari Yoshitane, Haruo Okado.

  Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4-5 months of age, and became impaired at 12-18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4-5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction.

Keywords:  Cognitive decline; DNA damage; DNA repair; Inflammation; Intellectual disability; ZBTB18/RP58

DOI:  https://doi.org/10.1186/s12974-024-03217-1
Eur J Pharmacol. 2024 Oct 15. pii: S0014-2999(24)00749-0. [Epub ahead of print] 177059

Polarized Macrophage functions are affected differentially after CSF-1R Inhibition with PLX5622.

Julia Barilo, Nasry Zane Bouzeineddine, Alecco Philippi, Sam Basta.

  PLX5622 is a colony stimulating factor 1 receptor (CSF-1R) inhibitor that is known to deplete microglial cells in vivo. Recently its effects on macrophages (Mφ) were also observed in vivo. Therefore, we performed this study to assess its in vitro effects on the differentiation and functions of polarized Mφ derived from different tissues. Our findings show that addition of PLX5622 early on after ex vivo isolation hinders Mφ differentiation and survival. However, its addition post Mφ differentiation did not significantly affect the viability. Furthermore, PLX5622 affects certain functions and degree of polarization of IL-4 (M2a) Mφ but not polarization of M1-like Mφ. Our study provides novel aspects on the application of PLX5622 to study Mφ functions in vitro, where polarization is affected by CSF-1R signalling and provides distinctive evidence to its ability to affect certain populations of Mφ during in vitro differentiation and maturation.

Keywords:  CSF-1R; M-CSF; cytokines; polarization

DOI:  https://doi.org/10.1016/j.ejphar.2024.177059
Transl Neurosci. 2024 Jan 01. 15(1): 20220352

Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein.

Duraisamy Kempuraj, Irene Tsilioni, Kristina K Aenlle, Nancy G Klimas, Theoharis C Theoharides.

   Objective: Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown. Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID.
Methods: In this study, MMP-9 was measured in the serum of long COVID patients and healthy controls, as well as in the supernatant fluid of cultured human microglia cell line stimulated by recombinant severe acute respiratory syndrome coronavirus 2 Spike protein, as well as lipopolysaccharide (LPS) and neurotensin (NT) used as positive controls. MMP-9 was measured by commercial enzyme-linked immunosorbent assay.
Results: MMP-9 was significantly elevated in the serum of long COVID patients compared to healthy controls. Moreover, there was significant release of MMP-9 from a cultured human microglia cell line stimulated by LPS, NT, or Spike protein. We further show that pretreatment with the flavonoids luteolin and tetramethoxyluteolin (methlut) significantly inhibited the release of MMP-9 stimulated by the Spike protein.
Conclusion: MMP-9 from Spike protein-stimulated microglia could contribute to the development of long COVID and may serve as a target for treatment including the use of luteolin.

Keywords:  MMP-9; brain inflammation; long COVID; luteolin; mast cells; microglia

DOI:  https://doi.org/10.1515/tnsci-2022-0352
Brain Res. 2024 Oct 12. pii: S0006-8993(24)00529-8. [Epub ahead of print] 149275

Microglia-astrocyte crosstalk is regulated by Astragalus polysaccharides mediated through suppression of Sema4D-PlexinB2 signaling in experimental autoimmune encephalomyelitis.

Jinyun Ma, Qijin Lu, Yan Zhao, Xiaohan Wang, Guiqing Ding, Yuanhua Wang, Xiaodong Cheng.

  The crosstalk between microglia inflamed in multiple sclerosis (MIMS) and astrocytes inflamed in MS (AIMS) is a crucial factor in the formation of the central inflammatory microenvironment and neurotoxicity. Astragalus polysaccharides (APS), an important bioactive component extracted from the dried root of Astragalus, was previously found by our team to attenuate the formation of pro-inflammatory microglia and neurological dysfunction in the experimental autoimmune encephalomyelitis (EAE) mice, a classic model of MS. To investigate the effect of APS on the MIMS-AIMS crosstalk and its underlying mechanism, in this study, a mouse model of EAE and a co-culture model of microglia-astrocytes in vitro were established. It was discovered that APS can alleviate the neurological dysfunction of EAE mice and effectively inhibit the formation of MIMS and AIMS both in vivo and in vitro. Furthermore, it was found that APS can suppress the inflammatory factors of MIMS-AIMS crosstalk in EAE mice and the resulting neurotoxicity in vivo and in vitro. The Sema4D-PlexinB2 signaling is essential for MIMS-AIMS crosstalk and promotes CNS inflammation. We demonstrated that APS can inhibit this signaling in vivo and in vitro. Treatment of recombinant Sema4D protein on cultured astrocytes in vitro significantly increases pro-inflammatory and neurotoxic factors, while APS significantly inhibits them. Conversely, after knockdown of Sema4D expression in microglia, APS no longer improves the neurotoxicity from MIMS-AIMS crosstalk. Overall, these results indicate that APS may modulate MIMS-AIMS crosstalk via the Sema4D-PlexinB2 signal. This study provides a scientific basis for APS as a potential treatment candidate for demyelinating diseases.

Keywords:  Astragalus polysaccharides; Experimental autoimmune encephalomyelitis; Microglia-astrocytes crosstalk; Neurotoxicity; Sema4D-PlexinB2 signaling

DOI:  https://doi.org/10.1016/j.brainres.2024.149275
J Neuroinflammation. 2024 Oct 18. 21(1): 262

Transient CSF1R inhibition ameliorates behavioral deficits in Cntnap2 knockout and valproic acid-exposed mouse models of autism.

Jiao Meng, Pengming Pan, Gengshuo Guo, Anqi Chen, Xiangbao Meng, Heli Liu.

  Microglial abnormality and heterogeneity are observed in autism spectrum disorder (ASD) patients and animal models of ASD. Microglial depletion by colony stimulating factor 1-receptor (CSF1R) inhibition has been proved to improve autism-like behaviors in maternal immune activation mouse offspring. However, it is unclear whether CSF1R inhibition has extensive effectiveness and pharmacological heterogeneity in treating autism models caused by genetic and environmental risk factors. Here, we report pharmacological functions and cellular mechanisms of PLX5622, a small-molecule CSF1R inhibitor, in treating Cntnap2 knockout and valproic acid (VPA)-exposed autism model mice. For the Cntnap2 knockout mice, PLX5622 can improve their social ability and reciprocal social behavior, slow down their hyperactivity in open field and repetitive grooming behavior, and enhance their nesting ability. For the VPA model mice, PLX5622 can enhance their social ability and social novelty, and alleviate their anxiety behavior, repetitive and stereotyped autism-like behaviors such as grooming and marble burying. At the cellular level, PLX5622 restores the morphology and/or number of microglia in the somatosensory cortex, striatum, and hippocampal CA1 regions of the two models. Specially, PLX5622 corrects neurophysiological abnormalities in the striatum of the Cntnap2 knockout mice, and in the somatosensory cortex, striatum, and hippocampal CA1 regions of the VPA model mice. Incidentally, microglial dynamic changes in the VPA model mice are also reported. Our study demonstrates that microglial depletion and repopulation by transient CSF1R inhibition is effective, and however, has differential pharmacological functions and cellular mechanisms in rescuing behavioral deficits in the two autism models.

Keywords:   Cntnap2 knockout mouse; Autism; CSF1R inhibitor; Microglia; Pharmacological heterogeneity; Valproic acid-exposed mouse

DOI:  https://doi.org/10.1186/s12974-024-03259-5
Int J Mol Sci. 2024 Oct 01. pii: 10594. [Epub ahead of print]25(19):

GSP1-111 Modulates the Microglial M1/M2 Phenotype by Inhibition of Toll-like Receptor 2: A Potential Therapeutic Strategy for Depression.

Ryeong-Eun Kim, Darine Froy Mabunga, Kyung-Jun Boo, Dong Hyun Kim, Seol-Heui Han, Chan Young Shin, Kyoung Ja Kwon.

  Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders.

Keywords:  depression; microglia; neuroinflammation; therapeutics; toll-like receptor 2

DOI:  https://doi.org/10.3390/ijms251910594
J Neurochem. 2024 Oct 10.

Proinflammatory microglial activation impairs in vitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor.

Diego R Hernandez-Espinosa, Gabriela I Medina-Ruiz, Mia G Scrabis, Amantha Thathiah, Elias Aizenman.

  Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.

Keywords:  ADAM17; CSF‐1R; mechanical injury; microglia activation; neuroinflammation; zinc

DOI:  https://doi.org/10.1111/jnc.16239
J Neuroinflammation. 2024 Oct 18. 21(1): 264

MAVS signaling shapes microglia responses to neurotropic virus infection.

Olivia Luise Gern, Andreas Pavlou, Felix Mulenge, Lena Mareike Busker, Luca Ghita, Angela Aringo, Bibiana Costa, Julia Spanier, Inken Waltl, Martin Stangel, Ulrich Kalinke.

  Viral encephalitis is characterized by a series of immunological reactions that can control virus infection in the brain, but dysregulated responses may cause excessive inflammation and brain damage. Microglia are brain-resident myeloid cells that are specialized in surveilling the local CNS environment and in case of viral brain infection they contribute to the control of the infection and to restriction of viral dissemination. Here, we report that after exposure to neurotropic vesicular stomatitis virus (VSV), murine in vitro microglia cultures showed rapid upregulation of a broad range of pro-inflammatory and antiviral genes, which were stably expressed over the entire 8 h infection period. Additionally, a set of immunomodulatory genes was upregulated between 6 and 8 h post infection. In microglia cultures, the induction of several immune response pathways including cytokine responses was dependent on mitochondrial antiviral-signaling protein (MAVS). Consequently, in Mavs-deficient microglia the control of virus propagation failed as indicated by augmented virus titers and the accumulation of viral transcripts. Thus, in the analyzed in vitro system, MAVS signaling is critically required to achieve full microglia activation and to mediate profound antiviral effects. In Mavs-deficient mice, intranasal VSV instillation caused higher disease severity than in WT mice and virus dissemination was noticed beyond the olfactory bulb. Virus spread to inner regions of the olfactory bulb, i.e., the granular cell layer, correlated with the recruitment of highly inflammatory non-microglia myeloid cells into the olfactory bulb in Mavs-/- mice. Furthermore, increased cytokine levels were detected in the nasal cavity, the olfactory bulb and in other brain regions. Thus, microglial MAVS signaling is critically needed for virus sensing, full microglia activation, and for orchestration of protective immunity in the virus-infected CNS.

Keywords:  CNS; Cardif; IPS-1; MAVS; Microglia; VISA; Virus

DOI:  https://doi.org/10.1186/s12974-024-03258-6