bims-microg 2024-11-03 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024‒11‒03
twenty-six papers selected by
Marcus Karlstetter, Universität zu Köln

Myocardial infarction augments sleep to limit cardiac inflammation and damage.
Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia.
Deep proteomic analysis of microglia reveals fundamental biological differences between model systems.
Microglia-derived Galectin-9 drives amyloid-β pathology in Alzheimer's disease.
Ethanol-activated microglial exosomes induce MCP1 signaling mediated death of stress-regulatory proopiomelanocortin neurons in the developing hypothalamus.
Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain.
Ganglion cell-derived LysoPS induces retinal neovascularisation by activating the microglial GPR34-PI3K-AKT-NINJ1 axis.
Withaferin a modulation of microglia autophagy mitigates neuroinflammation and enhances cognitive function in POCD.
Growing microglia in the lab.
Exploring Cellular Heterogeneity: Single-Cell and Spatial Transcriptomics of Alzheimer Disease Brains and iPSC-Derived Microglia.
Histamine stimulates human microglia to alter cellular prion protein expression via the HRH2 histamine receptor.
Proliferative Diabetic Retinopathy Microenvironment Drives Microglial Polarization and Promotes Angiogenesis and Fibrosis via Cyclooxygenase-2/Prostaglandin E2 Signaling.
Immune Checkpoint VISTA Negatively Regulates Microglia Glycolysis and Activation via TRIM28-Mediated Ubiquitination of HK2 in Sepsis-Associated Encephalopathy.
The emerging role of microglia in the development and therapy of multiple sclerosis.
α-Synuclein disrupts microglial autophagy through STAT1-dependent suppression of Ulk1 transcription.
Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways.
Brain inflammaging in the pathogenesis of late-life depression.
Lipidomics Analysis of Human HMC3 Microglial Cells in an In Vitro Model of Metabolic Syndrome.
Retinal ganglion cell circuits and glial interactions in humans and mice.
The Effect of Pexidartinib on Neuropathic Pain via Influences on Microglia and Neuroinflammation in Mice.
Ischemia-induced endogenous Nrf2/HO-1 axis activation modulates microglial polarization and restrains ischemic brain injury.
Phthalate exposure induces cell death and ferroptosis in neonatal microglial cells.
Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
Microglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders?
Fatty acid amide hydrolase gene inactivation induces hetero-cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease.

Nature. 2024 Oct 30.

Myocardial infarction augments sleep to limit cardiac inflammation and damage.

Pacific Huynh, Jan D Hoffmann, Teresa Gerhardt, Máté G Kiss, Faris M Zuraikat, Oren Cohen, Christopher Wolfram, Abi G Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Seonghun Yoon, Zhihong Chen, Vladimir Roudko, Travis Dawson, Joana Ferreira da Silva, Natalie J Ameral, Jarod Morgenroth-Rebin, Darwin D'Souza, Laura L Koekkoek, Walter Jacob, Jazz Munitz, Donghoon Lee, John F Fullard, Mandy M T van Leent, Panos Roussos, Seunghee Kim-Schulze, Neomi Shah, Benjamin P Kleinstiver, Filip K Swirski, David Leistner, Marie-Pierre St-Onge, Cameron S McAlpine.

Sleep is integral to cardiovascular health1,2. Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain's thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a-expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the β2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart's functional recovery. In parallel, insufficient sleep in humans reprogrammes β2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage.

DOI: https://doi.org/10.1038/s41586-024-08100-w
PLoS Biol. 2024 Oct;22(10): e3002819

Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia.

Hannah Gordon, Zachary T Schafer, Cody J Smith.

The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here, we show an additional feature of the developing nervous system that causes neural debris-promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood. Using transgenic zebrafish to investigate the microglia debris during brain construction, we identified that unlike other neural cell types that die in developmental stages after they have expanded, necroptosis-dependent microglial debris is prevalent when microglia are expanding in the zebrafish brain. Time-lapse imaging of microglia demonstrates that this debris is cannibalized by other microglia. To investigate features that promote microglia death and cannibalism, we used time-lapse imaging and fate-mapping strategies to track the lifespan of individual developmental microglia. These approaches revealed that instead of embryonic microglia being long-lived cells that completely digest their phagocytic debris, once most developmental microglia in zebrafish become phagocytic they eventually die, including ones that are cannibalistic. These results establish a paradox-which we tested by increasing neural debris and manipulating phagocytosis-that once most microglia in the embryo become phagocytic, they die, create debris, and then are cannibalized by other microglia, resulting in more phagocytic microglia that are destined to die.

DOI: https://doi.org/10.1371/journal.pbio.3002819
Cell Rep. 2024 Oct 25. pii: S2211-1247(24)01259-2. [Epub ahead of print]43(11): 114908

Deep proteomic analysis of microglia reveals fundamental biological differences between model systems.

Amy F Lloyd, Anna Martinez-Muriana, Emma Davis, Michael J D Daniels, Pengfei Hou, Renzo Mancuso, Alejandro J Brenes, Linda V Sinclair, Ivana Geric, An Snellinx, Katleen Craessaerts, Tom Theys, Mark Fiers, Bart De Strooper, Andrew J M Howden.

  Using high-resolution quantitative mass spectrometry, we present comprehensive human and mouse microglia proteomic datasets consisting of over 11,000 proteins across six microglia groups. Microglia share a core protein signature of over 5,600 proteins, yet fundamental differences are observed between species and culture conditions. Mouse microglia demonstrate proteome differences in inflammation- and Alzheimer's disease-associated proteins. We identify differences in the protein content of ex vivo and in vitro cells and significant proteome differences associated with protein synthesis, metabolism, microglia marker expression, and environmental sensors. Culturing microglia induces rapidly increased growth, protein content, and inflammatory protein expression. These changes are restored by engrafting in vitro cells into the brain, with xenografted human embryonic stem cell (hESC)-derived microglia closely resembling microglia from the human brain. These data provide an important resource for the field and highlight important considerations needed when using model systems to study human physiology and pathology of microglia.

Keywords:  CP: Neuroscience; Microglia; mass spectrometry; neuroimmunology; proteomics

DOI:  https://doi.org/10.1016/j.celrep.2024.114908
Aging Cell. 2024 Nov 01. e14396

Microglia-derived Galectin-9 drives amyloid-β pathology in Alzheimer's disease.

Guoxin Zhang, Qinyu Peng, Xiaodi Guo, Lina Pan, Min Xiong, Xingyu Zhang, Lijun Dai, Zhaohui Zhang, Tingting Xiao, Juanfeng He, Miao Liu, Wei Ke, Zhentao Zhang.

  The accumulation of amyloid-β (Aβ) and overactivation of microglia contribute to the pathogenesis of Alzheimer's disease (AD), but the interaction between microglial activation and Aβ deposition in AD remains elusive. Here we revealed that Aβ activates microglia and promotes the release of Galectin-9 (Gal-9), a member of the β-galactoside-binding family of lectins. The levels of Gal-9 in the cerebrospinal fluid and brain tissues of AD patients are higher than those in control subjects. Gal-9 interacts with Aβ and promotes its aggregation, generating Gal-9-Aβ fibrils with enhanced seeding activity and neurotoxicity. The expression of Gal-9 increases with age in the brains of APP/PS1 transgenic mice. Knockout of Gal-9 in APP/PS1 mice substantially reduced Aβ sedimentation, neuroinflammation, and cognitive impairment. Moreover, depletion of Gal-9 inhibited the seeding activity of brain homogenates from APP/PS1 mice. These findings reveal a mechanism by which microglia-derived Gal-9 accelerates Aβ aggregation and seeding in AD. Thus, strategies aimed at inhibiting Gal-9 may hold promise as a disease-modifying therapy to alleviate AD pathology.

Keywords:  Alzheimer's disease; amyloid‐β; cross‐seeding; galectin‐9; neuroinflammation

DOI:  https://doi.org/10.1111/acel.14396
J Neuroinflammation. 2024 Oct 30. 21(1): 279

Ethanol-activated microglial exosomes induce MCP1 signaling mediated death of stress-regulatory proopiomelanocortin neurons in the developing hypothalamus.

Prashant Tarale, Shaista Chaudhary, Sayani Mukherjee, Dipak K Sarkar.

  BACKGROUND: Microglia, a type of resident immune cells within the central nervous system, have been implicated in ethanol-activated neuronal death of the stress regulatory proopiomelanocortin (POMC) neuron-producing β-endorphin peptides in the hypothalamus in a postnatal rat model of fetal alcohol spectrum disorders. We determined if microglial extracellular vesicles (exosomes) are involved in the ethanol-induced neuronal death of the β-endorphin neuron via secreting elevated levels of the chemokine monocyte chemoattractant protein 1 (MCP1), a key regulator of neuroinflammation.METHODS: We employed an in vitro model, consisting of primary culture of hypothalamic microglia prepared from postnatal day 2 (PND2) rat hypothalami and treated with or without 50 mM ethanol for 24 h, and an in vivo animal model in which microglia were obtained from hypothalami of PND6 rats fed daily with 2.5 mg/kg ethanol or control milk formula for five days prior to use. Exosomes were extracted and characterized with nanosight tracking analysis (NTA), transmission electron microscopy and western blot. Chemokine multiplex immunoassay and ELISA were used for quantitative estimation of MCP1 level. Neurotoxic ability of exosome was tested using primary cultures of β-endorphin neurons and employing nucleosome assay and immunocytochemistry. Elevated plus maze, open field and restraint tests were used to assess anxiety-related behaviors.
RESULTS: Ethanol elevated MCP1 levels in microglial exosomes both in vitro and in vivo models. Ethanol-activated microglial exosomes when introduced into primary cultures of β-endorphin neurons, increased cellular levels of MCP1 and the chemokine receptor CCR2 related signaling molecules including inflammatory cytokines and apoptotic genes as well as apoptotic death of β-endorphin neurons. These effects of microglial exosomes on β-endorphin neurons were suppressed by a CCR2 antagonist RS504393. Furthermore, RS504393 when injected in postnatal rats prior to feeding with ethanol it reduced alcohol-induced β-endorphin neuronal death in the hypothalamus. RS504393 also suppressed corticosterone response to stress and anxiety-like behaviors in postnatally alcohol-fed rats during adult period.
CONCLUSION: These data suggest that alcohol exposures during the developmental period elevates MCP1 levels in microglial exosomes that promote MCP1/CCR2 signaling to increase the apoptosis of β-endorphin neurons and resulting in hormonal and behavioral stress responses.

Keywords:  CCR2; Developmental alcohol exposure; Exosomes; Fetal alcohol spectrum disorder; MCP1; Microglia; Neuronal apoptosis; Proopiomelanocortin neuron

DOI:  https://doi.org/10.1186/s12974-024-03274-6
Front Immunol. 2024 ;15 1440324

Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain.

Cordelia Dunai, Claire Hetherington, Sarah A Boardman, Jordan J Clark, Parul Sharma, Krishanthi Subramaniam, Kukatharmini Tharmaratnam, Edward J Needham, Robyn Williams, Yun Huang, Greta K Wood, Ceryce Collie, Andrew Fower, Hannah Fox, Mark A Ellul, Marie Held, Franklyn N Egbe, Michael Griffiths, Tom Solomon, Gerome Breen, Anja Kipar, Jonathan Cavanagh, Sarosh R Irani, Angela Vincent, James P Stewart, Leonie S Taams, David K Menon, Benedict D Michael.

  Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment.

Keywords:  SARS-CoV-2; immunology; microglia; neurology; virology

DOI:  https://doi.org/10.3389/fimmu.2024.1440324
J Neuroinflammation. 2024 Oct 28. 21(1): 278

Ganglion cell-derived LysoPS induces retinal neovascularisation by activating the microglial GPR34-PI3K-AKT-NINJ1 axis.

Lushu Chen, HuiYing Zhang, Ying Zhang, Xiumiao Li, MeiHuan Wang, Yaming Shen, Yuan Cao, Yong Xu, Jin Yao.

  Retinal neovascularisation is a major cause of blindness in patients with proliferative diabetic retinopathy (PDR). It is mediated by the complex interaction between dysfunctional ganglion cells, microglia, and vascular endothelial cells. Notably, retinal microglia, the intrinsic immune cells of the retina, play a crucial role in the pathogenesis of retinopathy. In this study, we found that lysophosphatidylserines (LysoPS) released from injured ganglion cells induced microglial extracellular trap formation and retinal neovascularisation. Mechanistically, LysoPS activated the GPR34-PI3K-AKT-NINJ1 signalling axis by interacting with the GPR34 receptor on the microglia. This activation upregulated the expression of inflammatory cytokines, such as IL-6, IL-8, VEGFA, and FGF2, and facilitated retinal vascular endothelial cell angiogenesis. As a result, inhibition of the GPR34-PI3K-AKT-NINJ1 axis significantly decreased microglial extracellular trap formation and neovascularisation by suppressing LysoPS-induced microglial inflammatory responses, both in vitro and in vivo. This study reveals the crucial role of apoptotic ganglion cells in activating microglial inflammation in PDR, thereby enhancing our understanding of the pathogenesis of retinal neovascularisation.

Keywords:  GPR34; LysoPS; Microglial extracellular traps; NINJ1; PI3K-AKT; Retinal neovascularisation

DOI:  https://doi.org/10.1186/s12974-024-03265-7
Sci Rep. 2024 10 30. 14(1): 26112

Withaferin a modulation of microglia autophagy mitigates neuroinflammation and enhances cognitive function in POCD.

Haijun Hu, Bingbing Cao, Dan Huang, Yue Lin, Bin Zhou, Jun Ying, Lelin Huang, Lieliang Zhang.

  With the aging process of the global population and the development of medical technology, the cases of postoperative cognitive dysfunction (POCD) are also increasing. Due to the complexity of the pathogenesis, urgent treatment has been sought. Neuroinflammation induced by the accumulation of lipid droplets (LDs) in microglia has been closely watched in recent years and is also considered to be an important cause of nerve damage. Our study found that derived from Withania somnifera, Withaferin A (WA) could reduce the accumulation of LDs in the hippocampus of POCD mice, inhibit the expression of inflammatory factor interleukin-1β (IL-1β), and improve the cognitive ability of mice. Further in vitro experimental studies showed that WA increased the autophagy level of microglia, promoted the degradation of LDs, and reduced the production of inflammatory factors. In this regard, our comprehensive research endeavor holds the potential to furnish novel insights into therapeutic strategies aimed at addressing POCD and its associated neural impairments.

Keywords:  LDs; Neuroinflammation; POCD; Withaferin A

DOI:  https://doi.org/10.1038/s41598-024-75284-6
Elife. 2024 Oct 28. pii: e103535. [Epub ahead of print]13

Growing microglia in the lab.

Jonathan M Levenson, Hio Tong Kam, Dong Feng Chen.

  Transplanting microglia derived from human stem cells into mice reveals new possibilities for treating neurodegenerative eye diseases.

Keywords:  Microglia; NaIO3; PLX-5622; RPE; human iPSC; mouse; regenerative medicine; retinal transplantation; stem cells

DOI:  https://doi.org/10.7554/eLife.103535
Res Sq. 2024 Oct 16. pii: rs.3.rs-5045715. [Epub ahead of print]

Exploring Cellular Heterogeneity: Single-Cell and Spatial Transcriptomics of Alzheimer Disease Brains and iPSC-Derived Microglia.

Anjali Garg, Sheeny Vo, Logan Brase, Ekaterina Aladyeva, Ricardo D'O Albanus, Aasritha Nallapu, Hongjun Fu, Oscar Harari.

Background Substantial evidence has established the critical role of microglia, the brain's resident immune cells, in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and understanding these states is crucial for elucidating the underlying mechanisms of AD. Methods In this work, we integrated single-cell and spatially resolved transcriptomics data from multiple cohorts and brain regions, including microglia from experimental and human brains. Results This comprehensive atlas revealed a great heterogeneity of microglial states, with a significant enrichment of specific states, including activated microglia, in AD brains compared to controls. Further integration of spatial transcriptomics and immunohistochemistry showed that activated microglia are predominantly located in the external cortical layers near amyloid plaques, while homeostatic microglia are more prevalent in the internal cortical layers and further away from the plaques. These spatial patterns were further validated using P2RY12 immunostaining, which confirmed the reliability of the transcriptomic data. Conclusion By integrating single-cell and spatial transcriptomics, we have provided a detailed atlas of microglial diversity, revealing the regional and pathological specificity of microglial states.

DOI: https://doi.org/10.21203/rs.3.rs-5045715/v1
Sci Rep. 2024 10 26. 14(1): 25519

Histamine stimulates human microglia to alter cellular prion protein expression via the HRH2 histamine receptor.

Marcus Pehar, Melissa Hewitt, Ashley Wagner, Jagdeep K Sandhu, Aria Khalili, Xinyu Wang, Jae-Young Cho, Valerie L Sim, Marianna Kulka.

  Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.

Keywords:  Degranulation; Histamine; Mast cell; Microglia; Neuroinflammation; Prion protein

DOI:  https://doi.org/10.1038/s41598-024-75982-1
Int J Mol Sci. 2024 Oct 21. pii: 11307. [Epub ahead of print]25(20):

Proliferative Diabetic Retinopathy Microenvironment Drives Microglial Polarization and Promotes Angiogenesis and Fibrosis via Cyclooxygenase-2/Prostaglandin E2 Signaling.

Shuta Kishishita, Ayumi Usui-Ouchi, Yasuo Ouchi, Yuiko Hata, Nobuyuki Ebihara, Shintaro Nakao.

  Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it may induce remain unclear. This study aimed to investigate the role of microglia in the progression of PDR under hypoxic and inflammatory conditions. We performed a comprehensive gene expression analysis using human-induced pluripotent stem cell-derived microglia under different stimuli (dimethyloxalylglycine (DMOG), lipopolysaccharide (LPS), and DMOG + LPS) to mimic the hypoxic inflammatory environment characteristic of PDR. Principal component analysis revealed distinct gene expression profiles, with 76 genes synergistically upregulated under combined stimulation. Notably, prostaglandin-endoperoxide synthase 2 (encoding cyclooxygenase (COX)-2) exhibited the most pronounced increase, leading to elevated prostaglandin E2 (PGE2) levels and driving pathological angiogenesis and inflammation via the COX-2/PGE2/PGE receptor 2 signaling axis. Additionally, the upregulation of the fibrogenic genes snail family transcriptional repressor 1 and collagen type I alpha 1 chain suggested a role for microglia in fibrosis. These findings underscore the critical involvement of microglia in PDR and suggest that targeting both the angiogenic and fibrotic pathways may present new therapeutic strategies for managing this condition.

Keywords:  COX-2; diabetic retinopathy; human microglia; hypoxia; inflammation; neurovascular unit

DOI:  https://doi.org/10.3390/ijms252011307
Mol Neurobiol. 2024 Oct 25.

Immune Checkpoint VISTA Negatively Regulates Microglia Glycolysis and Activation via TRIM28-Mediated Ubiquitination of HK2 in Sepsis-Associated Encephalopathy.

Yuhai Xu, Ying Zhu, Yue Shi, Bo Ye, Lulong Bo, Tianzhu Tao.

  V-domain immunoglobulin suppressor of T cell activation (VISTA) has emerged as a crucial player in the pathogenesis of neurological disorders. However, the specific mechanism by which VISTA regulates microglial activation remains unclear. Septic mice were intracerebroventricularly injected with an agonistic anti-VISTA antibody or isotype control. To investigate the differential gene expression profiles, RNA sequencing was conducted on brain tissues from these mice. In vitro, VISTA was silenced in BV2 microglial cells using shRNA. Co-immunoprecipitation assays were performed to identify protein-protein interactions involving hexokinase 2 (HK2), and ubiquitination assays were used to examine the ubiquitination status of HK2. Additionally, BV2 cells were transfected with either tripartite motif-containing 28 overexpression plasmids (TRIM28-PcDNA3.1( +)) or TRIM28-specific siRNA to assess the impact of TRIM28 on VISTA-mediated microglial activation. The cellular glycolytic activity was measured using extracellular acidification rate assays, and proinflammatory cytokine and chemokines were quantified. Treatment with VISTA antibodies significantly alleviated microglial activation and prevented cognitive impairment in septic mice. In contrast, VISTA silencing in BV2 microglia led to the overexpression of proinflammatory cytokines and enhanced glycolysis in an HK2-dependent manner. Mechanistically, HK2 expression was regulated by the E3 ubiquitin ligase TRIM28 through K63-linked ubiquitination, which targeted HK2 for proteasomal degradation. Furthermore, knockdown of TRIM28 reduced the elevated glycolysis and proinflammatory response observed in VISTA-silenced microglia. VISTA modulates microglial activation in sepsis-associated encephalopathy by regulating HK2 expression through TRIM28-mediated K63-linked ubiquitination. These findings highlight VISTA as a potential therapeutic target for modulating microglial activation in sepsis.

Keywords:  Hexokinase 2 (HK2); Microglia; Sepsis-associated encephalopathy (SAE); V-domain immunoglobulin suppressor of T cell activation (VISTA)

DOI:  https://doi.org/10.1007/s12035-024-04572-z
Int Immunopharmacol. 2024 Oct 29. pii: S1567-5769(24)01998-2. [Epub ahead of print]143(Pt 2): 113476

The emerging role of microglia in the development and therapy of multiple sclerosis.

Yunrong Nan, Shuting Ni, Mei Liu, Kaili Hu.

  Microglia are innate immune cells that maintain homeostasis of the central nervous system (CNS) and affect various neurodegenerative diseases, especially multiple sclerosis (MS). MS is an autoimmune disease of the CNS characterized by persistent inflammation, diffuse axonal damage, and microglia activation. Recent studies have shown that microglia are extremely related to the pathological state of MS and play an important role in the development of MS. This article reviews the multiple roles of microglia in the progression of MS, including the regulatory role of microglia in inflammation, remyelination, oxidative stress, the influence of phagocytosis and antigen-presenting capacity of microglia, and the recent progress by using microglia as a target for MS therapy. Microglia modulation may be a potential way for better MS therapy.

Keywords:  Inflammation; Microglia; Multiple sclerosis; Oxidative stress; Phagocytosis; Remyelination

DOI:  https://doi.org/10.1016/j.intimp.2024.113476
J Neuroinflammation. 2024 Oct 26. 21(1): 275

α-Synuclein disrupts microglial autophagy through STAT1-dependent suppression of Ulk1 transcription.

Chong-Shuang Pei, Xiao-Ou Hou, Zhen-Yuan Ma, Hai-Yue Tu, Hai-Chun Qian, Yang Li, Kai Li, Chun-Feng Liu, Liang Ouyang, Jun-Yi Liu, Li-Fang Hu.

  BACKGROUND: Autophagy dysfunction in glial cells is implicated in the pathogenesis of Parkinson's disease (PD). The previous study reported that α-synuclein (α-Syn) disrupted autophagy in cultured microglia. However, the mechanism of microglial autophagy dysregulation is poorly understood.METHODS: Two α-Syn-based PD models were generated via AAV-mediated α-Syn delivery into the mouse substantia nigra and striatal α-Syn preformed fibril (PFF) injection. The levels of microglial UNC-51-like kinase 1 (Ulk1) and other autophagy-related genes in vitro and in PD mice, as well as in the peripheral blood mononuclear cells of PD patients and healthy controls, were determined via quantitative PCR, western blotting and immunostaining. The regulatory effect of signal transducer and activator of transcription 1 (STAT1) on Ulk1 transcription was determined via a luciferase reporter assay and other biochemical studies and was verified through Stat1 knockdown or overexpression. The effect of α-Syn on glial STAT1 activation was assessed by immunohistochemistry and western blotting. Changes in microglial status, proinflammatory molecule expression and dopaminergic neuron loss in the nigrostriatum of PD and control mice following microglial Stat1 conditional knockout (cKO) or treatment with the ULK1 activator BL-918 were evaluated by immunostaining and western blotting. Motor behaviors were determined via open field tests, rotarod tests and balance beam crossing.
RESULTS: The transcription of microglial ULK1, a kinase that controls autophagy initiation, decreased in both in vitro and in vivo PD mouse models. STAT1 plays a critical role in suppressing Ulk1 transcription. Specifically, Stat1 overexpression downregulated Ulk1 transcription, while Stat1 knockdown increased ULK1 expression, along with an increase in LC3II and a decrease in the SQSTM1/p62 protein. α-Syn PFF caused toll-like receptor 4-dependent activation of STAT1 in microglia. Ablation of Stat1 alleviated the decrease in microglial ULK1 expression and disruption of autophagy caused by α-Syn PFF. Importantly, the ULK1 activator BL-918 and microglial Stat1 cKO attenuated neuroinflammation, dopaminergic neuronal damage and motor defects in PD models.
CONCLUSIONS: These findings reveal a novel mechanism by which α-Syn impairs microglial autophagy and indicate that targeting STAT1 or ULK1 may be a therapeutic strategy for PD.

Keywords:  Autophagy; Microglia; Parkinson’s disease; STAT1; ULK1; α-synuclein

DOI:  https://doi.org/10.1186/s12974-024-03268-4
J Neuroinflammation. 2024 Oct 27. 21(1): 276

Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways.

Julie Langlois, Simona Lange, Martin Ebeling, Will Macnair, Roland Schmucki, Cenxiao Li, Jonathan DeGeer, Tania J J Sudharshan, V Wee Yong, Yun-An Shen, Christopher Harp, Ludovic Collin, James Keaney.

  BACKGROUND: Bruton's tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B-lymphocyte and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, BTK inhibitors have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain-penetrant, small-molecule BTK inhibitors may also address compartmentalized neuroinflammation, which is proposed to underlie MS disease progression. BTK is expressed by microglia, which are the resident innate immune cells of the brain; however, the precise roles of microglial BTK and impact of BTK inhibitors on microglial functions are still being elucidated. Research on the effects of BTK inhibitors has been limited to rodent disease models. This is the first study reporting effects in human microglia.METHODS: Here we characterize the pharmacological and functional properties of fenebrutinib, a potent, highly selective, noncovalent, reversible, brain-penetrant BTK inhibitor, in human microglia and complex human brain cell systems, including brain organoids.
RESULTS: We find that fenebrutinib blocks the deleterious effects of microglial Fc gamma receptor (FcγR) activation, including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by fenebrutinib treatment. In contrast, fenebrutinib had no significant impact on human microglial pathways linked to Toll-like receptor 4 (TLR4) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) signaling or myelin phagocytosis.
CONCLUSIONS: Our study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS.

Keywords:  BTK; Fenebrutinib; Microglia; Multiple sclerosis; Neuroinflammation; Organoids

DOI:  https://doi.org/10.1186/s12974-024-03267-5
Hum Cell. 2024 Oct 26. 38(1): 7

Brain inflammaging in the pathogenesis of late-life depression.

Toshiaki Ishizuka, Wataru Nagata, Keiichi Nakagawa, Sayaka Takahashi.

  Late-life depression (LLD) is a prevalent mental disorder among older adults. Previous studies revealed that many pathologic factors are associated with the onset and development of LLD. However, the precise mechanisms that cause LLD remain elusive. Aging induces chronic inflammatory changes mediated by alterations of immune responses. The chronic systemic inflammation termed "inflammaging" is linked to the etiology of aging-related disorders. Aged microglia induce senescence-associated secretory phenotype (SASP) and transition to M1-phenotype, cause neuroinflammation, and diminish neuroprotective effects. In addition, there is an age-dependent loss of blood-brain barrier (BBB) integrity. As the BBB breakdown can lead to invasion of immune cells into brain parenchyma, peripheral immunosenescence may cause microglial activation and neuroinflammation. Therefore, it is suggested that these mechanisms related to brain inflammaging may be involved in the pathogenesis of LLD. In this review, we described the role of brain inflammaging in LLD. Pharmacologic approaches to prevent brain inflammaging appears to be a promising strategy for treating LLD.

Keywords:  BBB breakdown; Inflammasome activation; Late-life depression; Metabolic reprogramming; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1007/s13577-024-01132-4
Biomolecules. 2024 Sep 30. pii: 1238. [Epub ahead of print]14(10):

Lipidomics Analysis of Human HMC3 Microglial Cells in an In Vitro Model of Metabolic Syndrome.

Mateusz Chmielarz, Mariusz Aleksander Bromke, Mateusz Olbromski, Kamila Środa-Pomianek, Magdalena Frej-Mądrzak, Piotr Dzięgiel, Beata Sobieszczańska.

  Metabolic endotoxemia (ME) is associated with bacterial lipopolysaccharide (LPS, endotoxin) and increased levels of saturated fatty acids (SFAs) in the bloodstream, causing systemic inflammation. ME usually accompanies obesity and a diet rich in fats, especially SFAs. Numerous studies confirm the effect of ME-related endotoxin on microglial activation. Our study aimed to assess lipid metabolism and immune response in microglia pre-stimulated with TNFα (Tumor Necrosis Factor α) and then with endotoxin and palmitic acid (PA). Using ELISA, we determined cytokines IL-1β, IL-10, IL-13 (interleukin-1β, -10, -13, and TGFβ (Transforming Growth Factor β) in the culture medium from microglial cells stimulated for 24 h with TNFα and then treated with LPS (10 ng/mL) and PA (200 µM) for 24 h. HMC3 (Human Microglial Cells clone 3) cells produced negligible amounts of IL-1β, IL-10, and IL-13 after stimulation but secreted moderate levels of TGFβ. Changes in lipid metabolism accompanied changes in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) expression. HMC3 stimulation with endotoxin increased TREM2 expression, while PA treatment decreased it. Endotoxin increased ceramide levels, while PA increased triglyceride levels. These results indicated that pre-stimulation of microglia with TNFα significantly affects its interactions with LPS and PA and modulates lipid metabolism, which may lead to microglial activation silencing and neurodegeneration.

Keywords:  lipidomic analysis; metabolic syndrome; microglia

DOI:  https://doi.org/10.3390/biom14101238
Trends Neurosci. 2024 Oct 24. pii: S0166-2236(24)00182-6. [Epub ahead of print]

Retinal ganglion cell circuits and glial interactions in humans and mice.

Kang-Chieh Huang, Mohamed Tawfik, Melanie A Samuel.

  Retinal ganglion cells (RGCs) are the brain's gateway for vision, and their degeneration underlies several blinding diseases. RGCs interact with other neuronal cell types, microglia, and astrocytes in the retina and in the brain. Much knowledge has been gained about RGCs and glia from mice and other model organisms, often with the assumption that certain aspects of their biology may be conserved in humans. However, RGCs vary considerably between species, which could affect how they interact with their neuronal and glial partners. This review details which RGC and glial features are conserved between mice, humans, and primates, and which differ. We also discuss experimental approaches for studying human and primate RGCs. These strategies will help to bridge the gap between rodent and human RGC studies and increase study translatability to guide future therapeutic strategies.

Keywords:  astrocyte; development; microglia; organoid; retinal disease; vision

DOI:  https://doi.org/10.1016/j.tins.2024.09.010
Anesth Analg. 2024 Oct 30.

The Effect of Pexidartinib on Neuropathic Pain via Influences on Microglia and Neuroinflammation in Mice.

Liuyue Yang, Ashley Gomm, Ping Bai, Weihua Ding, Rudolph E Tanzi, Changning Wang, Shiqian Shen, Can Zhang.

BACKGROUND: Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties.METHOD: We used the previously reported chronic constriction injury (CCI) mouse model, in which PLX-3397 or vehicle was orally administrated to mice daily for 21 days, then applied to the CCI model, followed by PLX-3397 or vehicle administration for an additional 28 days. Additionally, we examined microglia-related neuroinflammation markers using positron emission tomography (PET) neuroimaging and immunofluorescence (IF).
RESULTS: We showed that PLX-3397 significantly ameliorated pain-related behavioral changes throughout the entire experimental period after CCI (vehicle versus PLX-3397 at day 14, effect size: 2.57, P = .002). Microglia changes were first analyzed by live-animal PET neuroimaging, revealing PLX-3397-associated reduction of microglia by probing receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein primarily expressed in microglia, which were further corroborated by postmortem immunohistochemistry (IHC) analysis using antibodies for microglia, including ionized Ca2+ binding adaptor molecule 1 (Iba-1) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 3.6, P = .011) and RIPK1 (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 2.9, P = .023. The expression of both markers decreased in the PLX-3397 group. Furthermore, we found that PLX-3397 led to significant reductions in various proteins, including inducible nitric oxide synthase (iNOS) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size: 2.3, P = .048), involved in neuroinflammation through IHC.
CONCLUSIONS: Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

DOI: https://doi.org/10.1213/ANE.0000000000007239
Front Immunol. 2024 ;15 1440592

Ischemia-induced endogenous Nrf2/HO-1 axis activation modulates microglial polarization and restrains ischemic brain injury.

Ping-Chang Kuo, Wen-Tsan Weng, Barbara A Scofield, Hallel C Paraiso, I-Chen Ivorine Yu, Jui-Hung Jimmy Yen.

  Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in the ischemic brain induce oxidative stress and inflammatory responses. Nrf2 is a transcription factor responsible for regulating cellular redox balance through the induction of protective antioxidant and phase II detoxification responses. Although the induction of endogenous Nrf2/HO-1 axis activation has been observed in the ischemic brain, whether ischemia-induced endogenous Nrf2/HO-1 axis activation plays a role in modulating microglia (MG) phenotypes and restraining ischemic brain injury is not characterized and requires further exploration. To investigate that, we generated mice with Nrf2 knockdown specifically in MG to rigorously assess the role of endogenous Nrf2 activation in ischemic brain injury after stroke. Our results showed that MG-specific Nrf2 knockdown exacerbated ischemic brain injury after stroke. We found that Nrf2 knockdown altered MG phenotypes after stroke, in which increased frequency of inflammatory MG and decreased frequency of anti-inflammatory MG were detected in the ischemic brain. Moreover, we identified attenuated Nrf2/HO-1 axis activation led to increased CD68/IL-1β and suppressed CD206 expression in MG, resulting in aggravated inflammatory MG in MG-specific Nrf2 knockdown mice after stroke. Intriguingly, using type II diabetic preclinical models, we revealed that diabetic mice exhibited attenuated Nrf2/HO-1 axis activation in MG and exacerbated ischemic brain injury after stroke that phenocopy mice with MG-specific Nrf2 knockdown. Finally, the induction of exogenous Nrf2/HO-1 axis activation in MG through pharmacological approaches ameliorated ischemic brain injury in diabetic mice. In conclusion, our findings provide cellular and molecular insights demonstrating ischemia-induced endogenous Nrf2/HO-1 axis activation modulates MG phenotypes and restrains ischemic brain injury. These results further strengthen the therapeutic potential of targeting Nrf2/HO-1 axis in MG for the treatment of ischemic stroke and diabetic stroke.

Keywords:  Nrf2/HO-1 axis; diabetic stroke; ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2024.1440592
Turk J Med Sci. 2024 ;54(5): 1102-1115

Phthalate exposure induces cell death and ferroptosis in neonatal microglial cells.

Elif Keleş, Arzu Aral, Zübeyir Elmazoğlu, Hasan Hüseyin Kazan, Elif Gülçiçek Abbasoğlu Topa, Mehmet Ali Ergün, Hayrunnisa Bolay.

  Background/aim: Phthalates are the materials used for plasticizing polyvinyl chloride. Di-(2-Ethylhexyl) phthalate (DEHP) is one of the phthalates most frequently used in a wide range of applications, including medical equipment such as endotracheal and feeding tubes, intravenous catheters, central lines, extracorporeal membrane oxygenation sets, total parenteral nutrition bags, blood product sets, and intravenous pump lines, respiratory sets in neonatal intensive care units (NICUs). Studies have shown that phthalates, including DEHP, can cross the placenta and blood-brain barrier, possibly leading to neurodevelopmental impairment in vitro and in vivo. However, the molecular mechanisms affected by phthalate exposure have not been explored in depth. This study aimed to illuminate the effects of DEHP on neuroinflammation at the molecular level using neonatal microglial cells as the model.Materials and methods: Mouse BV-2 neonatal microglia cells were exposed to DEHP under controlled conditions. Cellular toxicity was assessed via a cell viability assay and specific markers were used to evaluate the apoptosis/necrosis, cellular iron content, reactive oxygen species (ROS), and organelle integrity. Proinflammatory proteins were quantified using enzyme-linked immunosorbent assay, while ferroptosis was assessed using a ferroptosis blocker, and affected gene expressions were determined using quantitative reverse-transcriptase real-time polymerase chain reaction (RT-PCR).
Results: The results revealed that high concentrations of DEHP exposure increased toxicity via increased levels of ROS and inflammation. Elevated ROS levels were observed to increase the tendency for mitochondrial-lysosomal disruption, bringing about apoptosis or necrosis. Moreover, iron homeostasis was dysregulated by DEHP, which putatively triggered ferroptosis in a dose-dependent manner.
Conclusion: This study indicates that neonatal exposure to DEHP may be linked to neurodevelopmental impairment via inflammation-related cell death and ferroptosis. The prevalence of DEHP in NICU medical devices raises concerns about potential neurodevelopmental deficits, including disorders like autism and mental retardation. These findings highlight the urgency of addressing DEHP exposure in neonatal care.

Keywords:  DEHP; Phthalate; ferroptosis; inflammation; microglia

DOI:  https://doi.org/10.55730/1300-0144.5889
Mol Neurobiol. 2024 Nov 01.

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Nandi Bao, Jing Liu, Heran Wang, Lei Xing, Zhonghui Xie, Chuanbin Liu, Shaowei Jin, Jianjun Jia, Minghua Zhang, Jiao Fan.

  Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Keywords:  Drug repositioning analysis; Macrophage; Microglia; Multiple sclerosis; NMDA receptor inhibitors

DOI:  https://doi.org/10.1007/s12035-024-04602-w
bioRxiv. 2024 Oct 18. pii: 2024.10.15.618505. [Epub ahead of print]

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Alicia N Pietramale, Xhoela Bame, Megan E Doty, Robert A Hill.

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging of microglia mitochondria, revealing that microglial processes diverge, with some containing multiple mitochondria while others are completely void. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning and asymmetry between mitochondrial localization and cell process motility or acute damage responses.

DOI: https://doi.org/10.1101/2024.10.15.618505
Int J Mol Sci. 2024 Oct 11. pii: 10951. [Epub ahead of print]25(20):

Microglia Signatures: A Cause or Consequence of Microglia-Related Brain Disorders?

Alessandra Mirarchi, Elisabetta Albi, Cataldo Arcuri.

  Microglia signatures refer to distinct gene expression profiles or patterns of gene activity that are characteristic of microglia. Advances in gene expression profiling techniques, such as single-cell RNA sequencing, have allowed us to study microglia at a more detailed level and identify unique gene expression patterns that are associated, but not always, with different functional states of these cells. Microglial signatures depend on the developmental stage, brain region, and specific pathological conditions. By studying these signatures, it has been possible to gain insights into the underlying mechanisms of microglial activation and begin to develop targeted therapies to modulate microglia-mediated immune responses in the CNS. Historically, the first two signatures coincide with M1 pro-inflammatory and M2 anti-inflammatory phenotypes. The first one includes upregulation of genes such as CD86, TNF-α, IL-1β, and iNOS, while the second one may involve genes like CD206, Arg1, Chil3, and TGF-β. However, it has long been known that many and more specific phenotypes exist between M1 and M2, likely with corresponding signatures. Here, we discuss specific microglial signatures and their association, if any, with neurodegenerative pathologies and other brain disorders.

Keywords:  APOE; Alzheimer’s disease; TREM2; aging; microglia signatures; multiple sclerosis; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3390/ijms252010951
Glia. 2024 Oct 30.

Fatty acid amide hydrolase gene inactivation induces hetero-cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease.

María Andrea Arnanz, María Ferrer, María Teresa Grande, Samuel Ruiz de Martín Esteban, Gonzalo Ruiz-Pérez, Benjamin F Cravatt, Ricardo Mostany, Víctor Javier Sánchez-Arévalo Lobo, Julián Romero, Ana María Martínez-Relimpio.

  Neuroinflammation has recently emerged as a crucial factor in Alzheimer's disease (AD) etiopathogenesis. Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease-associated microglia (DAM) has offered new insights into the conflicting perspectives on the detrimental or beneficial roles of microglia. We previously showed that modulating the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in an amyloidosis context, paradoxically accompanied by an exacerbated neuroinflammatory response and the enrichment of DAM population. Here, we aim to elucidate the role of microglial cells in FAAH-lacking mice in the 5xFAD mouse model of AD by using RNA-sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH-lacking AD mice displayed upregulated inflammatory genes and exhibited a DAM genetic profile. Conversely, genes linked to AD were downregulated. Depleting microglia using PLX5622 revealed that plaque-associated microglia in FAAH-deficient AD mice had a more stable, ramified morphology and increased Aβ uptake, leading to reduced plaque growth compared to control mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the central nervous system. Our findings show that Faah gene inactivation triggers a hetero-cellular enhancement of microglial function that was paradoxically paralleled by an exacerbated inflammatory response. Taken together, the present data highlight FAAH as a potential therapeutic target in AD.

Keywords:  Alzheimer's disease; damage associated microglia; fatty acid amide hydrolase; microglia; neuroinflammation; two‐photon microscopy

DOI:  https://doi.org/10.1002/glia.24638