bims-microg 2024-08-25 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024‒08‒25
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease.
Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.
Microglia's heroic battle against neurodegeneration.
The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.
The enhancer RNA, AANCR, regulates APOE expression in astrocytes and microglia.
Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.
Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.
Transcriptomic analysis unveils bona fide molecular signatures of microglia under conditions of homeostasis and viral encephalitis.
Npc1 deficiency impairs microglia function via TREM2-mTOR signaling in Niemann-Pick disease type C.
The role of microglia in neuronal and cognitive function during high altitude acclimatization.
Deterioration of neuroimmune homeostasis in Alzheimer's Disease patients who survive a COVID-19 infection.
TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid.
ELK4 ameliorates cognitive impairment and neuroinflammation induced by obstructive sleep apnea.
"Let's talk about sex, inflammaging, and cognition, baby": A meta-analysis and meta-regression of 106 case-control studies on mild cognitive impairment and Alzheimer's disease.
Targeting microglial GLP1R in epilepsy: A novel approach to modulate neuroinflammation and neuronal apoptosis.
Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3.
Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.
Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity.
Brain volume and microglial density changes are correlated in a juvenile mouse model of cranial radiation and CSF1R inhibitor treatment.
The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy.
Microglial-mediated immune mechanisms in autoimmune uveitis: Elucidating pathogenic pathways and targeted therapeutics.
Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury.

Sci Transl Med. 2024 Aug 21. 16(761): eadm8563

Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease.

Simone Bido, Melania Nannoni, Sharon Muggeo, Diana Gambarè, Giorgia Ruffini, Edoardo Bellini, Laura Passeri, Silvia Iaia, Mirko Luoni, Martino Provinciali, Serena Gea Giannelli, Francesca Giannese, Dejan Lazarevic, Silvia Gregori, Vania Broccoli.

Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson's disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8+ T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.

DOI: https://doi.org/10.1126/scitranslmed.adm8563
Immunity. 2024 Aug 07. pii: S1074-7613(24)00368-6. [Epub ahead of print]

Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.

Emile Wogram, Felix Sümpelmann, Wentao Dong, Eshaan Rawat, Inés Fernández Maestre, Dongdong Fu, Brandyn Braswell, Andrew Khalil, Joerg M Buescher, Gerhard Mittler, Georg H H Borner, Andreas Vlachos, Stefan Tholen, Oliver Schilling, George W Bell, Angelika S Rambold, Asifa Akhtar, Oliver Schnell, Jürgen Beck, Monther Abu-Remaileh, Marco Prinz, Rudolf Jaenisch.

  Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis-and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions. Here, we developed a method for rapid isolation of pure and intact phagosomes from human pluripotent stem cell-derived microglia under various in vitro conditions, and from human brain biopsies, for unbiased multiomic analysis. Phagosome profiling revealed that microglial phagosomes were equipped to sense minute changes in their environment and were highly dynamic. We detected proteins involved in synapse homeostasis, or implicated in brain pathologies, and identified the phagosome as the site where quinolinic acid was stored and metabolized for de novo nicotinamide adenine dinucleotide (NAD+) generation in the cytoplasm. Our findings highlight the central role of phagosomes in microglial functioning in the healthy and diseased brain.

Keywords:  glioblastoma; human pluripotent stem cells; metabolomics; microglia; organelle; phagocytosis; phagosome; proteomics; quinolinic acid; synaptic pruning

DOI:  https://doi.org/10.1016/j.immuni.2024.07.019
Neuron. 2024 Aug 21. pii: S0896-6273(24)00538-5. [Epub ahead of print]112(16): 2661-2663

Microglia's heroic battle against neurodegeneration.

Yogita M Kattimani, Ari Waisman.

In this issue of Neuron, Chadarevian et al.1 and Munro et al.2 demonstrate how the absence of homeostatic microglia leads to severe neuropathologies, including axonal spheroids, calcifications, myelination abnormalities, and gliosis, associated with leukoencephalopathy and age-related neurodegeneration. Transplantation of healthy microglia can reverse these conditions, opening new avenues for therapeutic research.

DOI: https://doi.org/10.1016/j.neuron.2024.07.016
J Neuroinflammation. 2024 Aug 20. 21(1): 207

The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.

Melanie Ohm, Shirin Hosseini, Niklas Lonnemann, Wei He, Tushar More, Oliver Goldmann, Eva Medina, Karsten Hiller, Martin Korte.

  Despite advances in antimicrobial and anti-inflammatory treatment, inflammation and its consequences remain a major challenge in the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic inflammation has the potential to worsen the condition of body tissues and ultimately lead to significant impairment of their functionality. Although the central nervous system has long been considered immune privileged to peripheral immune responses, recent research has shown that strong immune responses in the periphery also affect the brain, leading to reactive microglia, which belong to the innate immune system and reside in the brain, and neuroinflammation. The inflammatory response is primarily a protective mechanism to defend against pathogens and tissue damage. However, excessive and chronic inflammation can have negative effects on neuronal structure and function. Neuroinflammation underlies the pathogenesis of many neurological and neurodegenerative diseases and can accelerate their progression. Consequently, targeting inflammatory signaling pathways offers potential therapeutic strategies for various neuropathological conditions, particularly Parkinson's and Alzheimer's disease, by curbing inflammation. Here the blood-brain barrier is a major hurdle for potential therapeutic strategies, therefore it would be highly advantageous to foster and utilize brain innate anti-inflammatory mechanisms. The tricarboxylic acid cycle-derived metabolite itaconate is highly upregulated in activated macrophages and has been shown to act as an immunomodulator with anti-inflammatory and antimicrobial functions. Mesaconate, an isomer of itaconate, similarly reduces the inflammatory response in macrophages. Nevertheless, most studies have focused on its esterified forms and its peripheral effects, while its influence on the CNS remained largely unexplored. Therefore, this study investigated the immunomodulatory and therapeutic potential of endogenously synthesized itaconate and its isomer mesaconate in lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show that both itaconate and mesaconate reduce LPS-induced neuroinflammation, as evidenced by lower levels of inflammatory mediators, reduced microglial reactivity and a rescue of synaptic plasticity, the cellular correlate of learning and memory processes in the brain. Overall, this study emphasizes that both itaconate and mesaconate have therapeutic potential for neuroinflammatory processes in the brain and are of remarkable importance due to their endogenous origin and production, which usually leads to high tolerance.

Keywords:  Hippocampus; LPS; Microglia; Neuroinflammation; Synaptic plasticity

DOI:  https://doi.org/10.1186/s12974-024-03188-3
Nucleic Acids Res. 2024 Aug 20. pii: gkae696. [Epub ahead of print]

The enhancer RNA, AANCR, regulates APOE expression in astrocytes and microglia.

Ma Wan, Yaojuan Liu, Dongjun Li, Ryan J Snyder, Lillian B Elkin, Christopher R Day, Joseph Rodriguez, Christopher Grunseich, Robert W Mahley, Jason A Watts, Vivian G Cheung.

Enhancers, critical regulatory elements within the human genome, are often transcribed into enhancer RNAs. The dysregulation of enhancers leads to diseases collectively termed enhanceropathies. While it is known that enhancers play a role in diseases by regulating gene expression, the specific mechanisms by which individual enhancers cause diseases are not well understood. Studies of individual enhancers are needed to fill this gap. This study delves into the role of APOE-activating noncoding RNA, AANCR, in the central nervous system, elucidating its function as a genetic modifier in Alzheimer's Disease. We employed RNA interference, RNaseH-mediated degradation, and single-molecule RNA fluorescence in situ hybridization to demonstrate that mere transcription of AANCR is insufficient; rather, its transcripts are crucial for promoting APOE expression. Our findings revealed that AANCR is induced by ATM-mediated ERK phosphorylation and subsequent AP-1 transcription factor activation. Once activated, AANCR enhances APOE expression, which in turn imparts an inflammatory phenotype to astrocytes. These findings demonstrate that AANCR is a key enhancer RNA in some cell types within the nervous system, pivotal for regulating APOE expression and influencing inflammatory responses, underscoring its potential as a therapeutic target in neurodegenerative diseases.

DOI: https://doi.org/10.1093/nar/gkae696
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2406005121

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.

Robin Bonomi, Ansel T Hillmer, Eric Woodcock, Shivani Bhatt, Aleksandra Rusowicz, Gustavo A Angarita, Richard E Carson, Margaret T Davis, Irina Esterlis, Nabeel Nabulsi, Yiyun Huang, John H Krystal, Robert H Pietrzak, Kelly P Cosgrove.

  Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Keywords:  PET; PTSD; TSPO; neuroimmune

DOI:  https://doi.org/10.1073/pnas.2406005121
Sci Adv. 2024 Aug 23. 10(34): eadn4845

Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.

Jiaqi Liu, Yue Liang, Qinghao Meng, Jiayu Chen, Junwei Ma, Hong Zhu, Lei Cai, Nanshan Song, Jianhua Ding, Yi Fan, Ming Lu, Guangyu Wu, Yinquan Fang, Gang Hu.

Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.

DOI: https://doi.org/10.1126/sciadv.adn4845
J Neuroinflammation. 2024 Aug 17. 21(1): 203

Transcriptomic analysis unveils bona fide molecular signatures of microglia under conditions of homeostasis and viral encephalitis.

Felix Mulenge, Olivia Luise Gern, Lena Mareike Busker, Angela Aringo, Luca Ghita, Inken Waltl, Andreas Pavlou, Ulrich Kalinke.

Microglia serve as a front-line defense against neuroinvasive viral infection, however, determination of their actual transcriptional profiles under conditions of health and disease is challenging. Here, we used various experimental approaches to delineate the transcriptional landscape of microglia during viral infection. Intriguingly, multiple activation genes were found to be artificially induced in sorted microglia and we demonstrated that shear stress encountered during cell sorting was one of the key inducers. Post-hoc analysis revealed that publicly available large-scale single-cell RNA sequencing datasets were significantly tainted by aberrant signatures that are associated with cell sorting. By exploiting the ribosomal tagging approach, we developed a strategy to enrich microglia-specific transcripts by comparing immunoprecipitated RNA with total RNA. Such enriched transcripts were instrumental in defining bona fide signatures of microglia under conditions of health and virus infection. These unified microglial signatures may serve as a benchmark to retrospectively assess ex vivo artefacts from available atlases. Leveraging the microglial translatome, we found enrichment of genes implicated in T-cell activation and cytokine production during the course of VSV infection. These data linked microglia with T-cell re-stimulation and further underscored that microglia are involved in shaping antiviral T-cell responses in the brain. Collectively, our study defines the transcriptional landscape of microglia under steady state and during viral encephalitis and highlights cellular interactions between microglia and T cells that contribute to the control of virus dissemination.

DOI: https://doi.org/10.1186/s12974-024-03197-2
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 20. pii: S0925-4439(24)00472-1. [Epub ahead of print] 167478

Npc1 deficiency impairs microglia function via TREM2-mTOR signaling in Niemann-Pick disease type C.

Liang Qiao, Xiaojing Han, Ru Ding, Xiaodi Shang, Lulu Xiao, Ge Gao, Chu Zhang, Jing Kang, Xi Su, Yanli Liu, Jiankai Luo, Xin Yan, Juntang Lin.

  Niemann-Pick disease Type C (NPC) is a neurodegenerative disease mainly caused by the mutation in NPC1 gene, leading to massive accumulation of unesterified cholesterol in the late endosome/lysosome of cells. Impaired phenotype of microglia is a hallmark in Npc1 mutant mice (Npc1-/- mice). However, the mechanism of Npc1 in regulating microglial function is still unclear. Here, we showed that the reactive microglia in the neonatal Npc1-/- mice indicated by the increased lysosome protein CD68 and phagocytic activity were associated with disrupted TREM2-mTOR signaling in microglia. Furthermore, in Npc1-deficient BV2 cells, genetic deletion of Trem2 partially restored microglial function, probably via restored mTOR signaling. Taken together, our findings indicated that loss of Npc1 in microglia caused changes of their morphologies and the impairment of lysosomal function, which were linked to the TREM2-mTOR signaling pathway.

Keywords:  Development; Microglia; Npc1; TREM2; mTOR

DOI:  https://doi.org/10.1016/j.bbadis.2024.167478
Sci Rep. 2024 08 16. 14(1): 18981

The role of microglia in neuronal and cognitive function during high altitude acclimatization.

Kathleen Hatch, Fritz Lischka, Mengfan Wang, Xiufen Xu, Cheryl D Stimpson, Tara Barvir, Nathan P Cramer, Daniel P Perl, Guoqiang Yu, Caroline A Browne, Dara L Dickstein, Zygmunt Galdzicki.

  Due to their interactions with the neurovasculature, microglia are implicated in maladaptive responses to hypobaric hypoxia at high altitude (HA). To explore these interactions at HA, pharmacological depletion of microglia with the colony-stimulating factor-1 receptor inhibitor, PLX5622, was employed in male C57BL/6J mice maintained at HA or sea level (SL) for 3-weeks, followed by assessment of ex-vivo hippocampal long-term potentiation (LTP), fear memory recall and microglial dynamics/physiology. Our findings revealed that microglia depletion decreased LTP and reduced glucose levels by 25% at SL but did not affect fear memory recall. At HA, the absence of microglia did not significantly alter HA associated deficits in fear memory or HA mediated decreases in peripheral glucose levels. In regard to microglial dynamics in the cortex, HA enhanced microglial surveillance activity, ablation of microglia resulted in increased chemotactic responses and decreased microglia tip proliferation during ball formation. In contrast, vessel ablation increased cortical microglia tip path tortuosity. In the hippocampus, changes in microglial dynamics were only observed in response to vessel ablation following HA. As the hippocampus is critical for learning and memory, poor hippocampal microglial context-dependent adaptation may be responsible for some of the enduring neurological deficits associated with HA.

Keywords:  High altitude; Microglia; Microglial heterogeneity; Neurovasculature

DOI:  https://doi.org/10.1038/s41598-024-69694-9
J Neuroinflammation. 2024 Aug 17. 21(1): 202

Deterioration of neuroimmune homeostasis in Alzheimer's Disease patients who survive a COVID-19 infection.

Jonathan A B Villareal, Tim Bathe, Gabriela P Hery, Jennifer L Phillips, Wangchen Tsering, Stefan Prokop.

  Growing evidence has implicated systemic infection as a significant risk factor for the development and advancement of Alzheimer's disease (AD). With the emergence of SARS-CoV-2 (COVID-19) and the resultant pandemic, many individuals from the same aging population vulnerable to AD suffered a severe systemic infection with potentially unidentified long-term consequences for survivors. To study the impact of COVID-19 survival on the brain's intrinsic immune system in a population also suffering from AD, we profiled post-mortem brain tissue from patients in the UF Neuromedicine Human Brain and Tissue Bank with a diagnosis of AD who survived a COVID-19 infection (COVID-AD) and contrasted our findings with AD patients who did not experience a COVID-19 infection, including a group of brain donors who passed away before arrival of SARS-CoV-2 in the United States. We assessed disease-relevant protein pathology and microglial and astrocytic markers by quantitative immunohistochemistry and supplemented these data with whole tissue gene expression analysis performed on the NanoString nCounter® platform. COVID-AD patients showed slightly elevated Aβ burden in the entorhinal, fusiform, and inferior temporal cortices compared to non-COVID-AD patients, while tau pathology burden did not differ between groups. Analysis of microglia revealed a significant loss of microglial homeostasis as well as exacerbated microgliosis in COVID-AD patients compared to non-COVID-AD patients in a brain region-dependent manner. Furthermore, COVID-AD patients showed reduced cortical astrocyte numbers, independent of functional subtype. Transcriptomic analysis supported these histological findings and, in addition, identified a dysregulation of oligodendrocyte and myelination pathways in the hippocampus of COVID-AD patients. In summary, our data demonstrate a profound impact of COVID-19 infection on neuroimmune and glial pathways in AD patients persisting for months post-infection, highlighting the importance of peripheral to central neuroimmune crosstalk in neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Astrocytes; COVID-19; Microglia; Neuroinflammation; Oligodendrocytes; Systemic infection

DOI:  https://doi.org/10.1186/s12974-024-03196-3
J Biol Chem. 2024 Aug 17. pii: S0021-9258(24)02192-6. [Epub ahead of print] 107691

TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid.

Ilayda Ozsan McMillan, Li Liang, Guowei Su, Xuehong Song, Kelly Drago, Hua Yang, Claudia Alvarez, Amika Sood, James Gibson, Robert J Woods, Chunyu Wang, Jian Liu, Fuming Zhang, Tom J Brett, Lianchun Wang.

  The Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 binary complexes on microglia cell surfaces. Employing various biochemical techniques, including Surface Plasmon Resonance, low molecular weight HS microarray screening, and serial HS mutant cell surface binding assays, we demonstrate TREM2's robust affinity for HS, and the effective binding requires a minimum HS size of approximately 10 saccharide units. Notably, TREM2 selectively binds specific HS structures, with 6-O-sulfation and, to a lesser extent, the iduronic acid residue playing crucial roles. N-sulfation and 2-O-sulfation are dispensable for this interaction. Furthermore, we reveal that 6-O-sulfation is essential for HS-TREM2 ternary complex formation on the microglial cell surface, and HS and its 6-O-sulfation are necessary for TREM2-mediated ApoE3 uptake in microglia. By delineating the interaction between HS and TREM2 on the microglial cell surface and demonstrating its role in facilitating TREM2-mediated ApoE uptake by microglia, our findings provide valuable insights that can inform targeted interventions for modulating microglial functions in Alzheimer's disease.

Keywords:  TREM2; binary complex; heparan sulfate; microglia; structure-function

DOI:  https://doi.org/10.1016/j.jbc.2024.107691
Brain Res Bull. 2024 Aug 20. pii: S0361-9230(24)00188-6. [Epub ahead of print] 111054

ELK4 ameliorates cognitive impairment and neuroinflammation induced by obstructive sleep apnea.

Haiming Yang, Ying Yuan, Ke Yang, Ning Wang, Xiao Li.

  Intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) syndrome elicited neuron injury (especially in the hippocampus and cortex), contributing to cognitive dysfunction. This study investigated the effects and clarified the mechanisms of ETS domain-containing protein Elk-4 (ELK4) on the cognitive function and neuroinflammation of mice with IH. Mouse microglia BV2 cells were induced with IH by exposure to fluctuating O2 concentrations (alternating from 5% to 21% every 30min), and mice with OSA were developed and subjected to lentivirus-mediated gene intervention. ELK4 expression was significantly reduced in IH-induced microglia and brain tissues of mice with OSA. Overexpression of ELK4 attenuated oxidative stress, decreased the pro-inflammatory factors IL-1β, IL-6, and TNF-α, and increased the level of the anti-inflammatory factors IL-10 and TGF-β1, as well as the neuroprotective factor BDNF. ELK4 promoted the transcription of fibronectin type III domain-containing protein 5 (FNDC5) by binding to the promoter of FNDC5. Knockdown of FNDC5 in IH-induced microglia and animals reversed the protective effects of ELK4 on OSA-associated neuroinflammation and cognitive dysfunction. Overall, the results demonstrated that ELK4 overexpression repressed microglial activation by inducing the transcription of FNDC5, thus attenuating neuroinflammation and cognitive dysfunction induced by OSA.

Keywords:  Cognitive dysfunction; ELK4; FNDC5; Microglia; Obstructive sleep apnea syndrome

DOI:  https://doi.org/10.1016/j.brainresbull.2024.111054
Brain Behav Immun Health. 2024 Oct;40 100819

"Let's talk about sex, inflammaging, and cognition, baby": A meta-analysis and meta-regression of 106 case-control studies on mild cognitive impairment and Alzheimer's disease.

Ryan Childs, Diana Karamacoska, Chai K Lim, Genevieve Z Steiner-Lim.

  Background: Chronic inflammation is recognised as an important component of Alzheimer's disease (AD), yet its relationship with cognitive decline, sex-differences, and age is not well understood. This study investigated the relationship between inflammatory markers, cognition, sex, and age in individuals with mild cognitive impairment (MCI) and AD.Methods: A systematic review was performed to identify case-control studies which measured cognitive function and inflammatory markers in serum, plasma, and cerebrospinal fluid in individuals with MCI or AD compared with healthy control (HC) participants. Meta-analysis was performed with Hedges' g calculated in a random effects model. Meta-regression was conducted using age, sex, and mini-mental status exam (MMSE) values.
Results: A total of 106 studies without a high risk of bias were included in the meta-analysis including 18,145 individuals: 5625 AD participants, 3907 MCI participants, and 8613 HC participants. Combined serum and plasma meta-analysis found that IL1β, IL6, IL8, IL18, CRP, and hsCRP were significantly raised in individuals with AD compared to HC. In CSF, YKL40, and MCP-1 were raised in AD compared to HC. YKL40 was also raised in MCI compared to HC. Meta-regression analysis highlighted several novel findings: MMSE was negatively correlated with IL6 and positively correlated with IL1α in AD, while in MCI studies, MMSE was negatively correlated with IL8 and TNFα. Meta-regression also revealed sex-specific differences in levels of IL1α, IL4, IL6, IL18, hsCRP, MCP-1, and YKL-40 across AD and MCI studies, and age was found to account for heterogeneity of CRP, MCP-1, and IL4 in MCI and AD.
Conclusion: Elevated levels of IL6 and YKL40 may reflect microglial inflammatory activity in both MCI and AD. Systemic inflammation may interact with the central nervous system, as poor cognitive function in individuals with AD and MCI was associated with higher levels of serum and plasma proinflammatory cytokines IL6 and TNFα. Moreover, variations of systemic inflammation between males and females may be modulated by sex-specific hormonal changes, such as declining oestrogen levels in females throughout the menopause transition. Longitudinal studies sampling a range of biospecimen types are needed to elucidate the nuances of the relationship between inflammation and cognition in individuals with MCI and AD, and understand how systemic and central inflammation differentially impact cognitive function.

Keywords:  Alzheimer's disease; Cognition; Inflammation; Meta-regression; Microglia; Mild cognitive impairment (MCI); Sex-differences

DOI:  https://doi.org/10.1016/j.bbih.2024.100819
Eur J Pharmacol. 2024 Aug 16. pii: S0014-2999(24)00592-2. [Epub ahead of print]981 176903

Targeting microglial GLP1R in epilepsy: A novel approach to modulate neuroinflammation and neuronal apoptosis.

Kai Zhang, Zhiquan Yang, Zhuanyi Yang, Liangchao Du, Yu Zhou, Shiyu Fu, Xiaoyue Wang, Dingyang Liu, Xinghui He.

  BACKGROUND: Epilepsy is a prevalent disorder of the central nervous system. Approximately, one-third of patients show resistance to pharmacological interventions. The pathogenesis of epilepsy is complex, and neuronal apoptosis plays a critical role. Aberrantly reactive astrocytes, induced by cytokine release from activated microglia, may lead to neuronal apoptosis. This study investigated the role of glucagon-like peptide 1 receptor (GLP1R) in microglial activation in epilepsy and its impact on astrocyte-mediated neurotoxicity.METHODS: We used human hippocampal tissue from patients with temporal lobe epilepsy and a pilocarpine-induced epileptic mouse model to assess neurobiological changes in epilepsy. BV2 microglial cells and primary astrocytes were used to evaluate cytokine release and astrocyte activation in vitro. The involvement of GLP1R was explored using the GLP1R agonist, Exendin-4 (Ex-4).
RESULTS: Our findings indicated that reduced GLP1R expression in hippocampal microglia in both epileptic mouse models and human patients, correlated with increased cytokine release and astrocyte activation. Ex-4 treatment restored microglial homeostasis, decreased cytokine secretion, and reduced astrocyte activation, particularly of the A1 phenotype. These changes were associated with a reduction in neuronal apoptosis. In addition, Ex-4 treatment significantly decreased the frequency and duration of seizures in epileptic mice.
CONCLUSIONS: This study highlights the crucial role of microglial GLP1R in epilepsy pathophysiology. GLP1R downregulation contributes to microglial- and astrocyte-mediated neurotoxicity, exacerbating neuronal death and seizures. Activation of GLP1R with Ex-4 has emerged as a promising therapeutic strategy to reduce neuroinflammation, protect neuronal cells, and control seizures in epilepsy. This study provides a foundation for developing novel antiepileptic therapies targeting microglial GLP1R, with the potential to improve outcomes in patients with epilepsy.

Keywords:  A1 astrocyte; Activated microglia; Epileptic mice; Exendin-4; GLP1R; Glia-crosstalk; Homeostatic microglia; Neuronal apoptosis; Neuronal protection; Reactive astrocytes

DOI:  https://doi.org/10.1016/j.ejphar.2024.176903
Inflammation. 2024 Aug 23.

Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3.

Xuliang Huang, Yuhao Zheng, Nan Wang, Mingming Zhao, Jinhui Liu, Wen Lin, Ye Zhu, Xiaofan Xie, Ya Lv, Junlu Wang, Yunchang Mo.

  Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, is often used to treat lactic acidosis and malignant tumors. Increasing studies have shown that DCA has neuroprotective effects. Here, we explored the role and mechanism of DCA in Sepsis associated encephalopathy (SAE). Single-cell analysis was used to determine the important role of PDK4 in SAE and identify the cell type. GO and GSEA analysis were used to determine the correlation between DCA and pyroptosis. Through LPS + ATP stimulation, a microglia pyroptosis model was established to observe the expression level of intracellular pyroptosis-related proteins under DCA intervention, and further detect the changes in intracellular ROS and JC-1. Additionally, a co-culture environment of microglia and neuron was simply constructed to evaluate the effect of DCA on activated microglia-mediated neuronal apoptosis. Finally, Novel object recognition test and the Morris water maze were used to explore the effect of DCA on cognitive function in mice from different groups after intervention. Based on the above experiments, this study concludes that DCA can improve the ratio of peripheral and central M1 macrophages, inhibit NLRP3-mediated pyroptosis through ROS and mitochondrial membrane potential (MMP). DCA can reduce neuron death caused by SAE and improve cognitive function in LPS mice. In SAE, DCA may be a potential candidate drug for the treatment of microglia-mediated neuroinflammation.

Keywords:  DCA; PDK4; pyroptosis; sepsis-associated encephalopathy

DOI:  https://doi.org/10.1007/s10753-024-02105-3
Brain Behav Immun. 2024 Aug 18. pii: S0889-1591(24)00555-5. [Epub ahead of print]

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Aleksandr Birg, Harm J van der Horn, Sephira G Ryman, Francesca Branzoli, Dinesh K Deelchand, Davin K Quinn, Andrew R Mayer, Henry C Lin, Erik B Erhardt, Arvind Caprihan, Vadim Zotev, Alisha N Parada, Tracey V Wick, Yvette L Matos, Kimberly A Barnhart, Stephanie R Nitschke, Nicholas A Shaff, Kayla R Julio, Haley E Prather, Andrei A Vakhtin.

  Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial neurometabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Keywords:  Corona radiata; Diffusion weighted magnetic resonance spectroscopy (dMRS); Gut-brain; Innate immune system; Microglia; Microglial activation; Microglial reactivity; Neuroinflammation; Thalamus; lipopolysaccharide (LPS)

DOI:  https://doi.org/10.1016/j.bbi.2024.08.034
Mol Neurobiol. 2024 Aug 19.

Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity.

Austin N Smith, Alison Gregor, Lisa Baker, David J Sharp, Kimberly R Byrnes.

  The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1β, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses.

Keywords:  Cytokine secretion; Cytoskeleton; FIGNL2; Microtubule dynamics; Motility; Nanoparticle siRNA; Phagocytosis

DOI:  https://doi.org/10.1007/s12035-024-04404-0
NMR Biomed. 2024 Aug 20. e5222

Brain volume and microglial density changes are correlated in a juvenile mouse model of cranial radiation and CSF1R inhibitor treatment.

Ramy Ayoub, Sabrina Yang, Helen Ji, Lloyd Fan, Steven De Michino, Donald J Mabbott, Brian J Nieman.

  Microglia have been shown to proliferate and become activated following cranial radiotherapy (CRT), resulting in a chronic inflammatory response. We investigated the role of microglia in contributing to widespread volume losses observed in the brain following CRT in juvenile mice. To manipulate microglia, we used low-dose treatment with a highly selective CSF1R inhibitor called PLX5622 (PLX). We hypothesized that alteration of the post-CRT microglia population would lead to changes in brain development outcomes, as evaluated by structural MRI. Wild-type C57BL/6J mice were provided with daily intraperitoneal injections of PLX (25 mg/kg) or vehicle from postnatal day (P)14 to P19. Mice also received whole-brain irradiation (7 Gy) or sham irradiation (0 Gy) at 16 days of age. In one cohort of mice, immunohistochemical assessment in tissue sections was conducted to assess the impact of the selected PLX and CRT doses as well as their combination. In a separate cohort, mice were imaged using MRI at P14 (pretreatment), P19, P23, P42 and P63 in order to assess induced volume changes, which were measured based on structures from a predefined atlas. We observed that PLX and radiation treatments led to sex-specific changes in the microglial cell population. Across treatment groups, MRI-detected anatomical volumes at P19 and P63 were associated with microglia and proliferating microglia densities, respectively. Overall, our study demonstrates that low-dose PLX treatment produces a sex-dependent response in juvenile mice, that manipulation of microglia alters CRT-induced volume changes and that microglia density and MRI-derived volume changes are correlated in this model.

Keywords:  CSF1R inhibitor; cranial radiotherapy; microglia; pediatric brain tumors; sex effects

DOI:  https://doi.org/10.1002/nbm.5222
Gene. 2024 Aug 15. pii: S0378-1119(24)00742-X. [Epub ahead of print]930 148861

The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy.

Qiang Hu, Xue Zhang, Jiayang Huang, Hongsong Peng, Yage Sun, Wei Sang, Bo Jiang, Dawei Sun.

  BACKGROUND: By identifying molecular biological markers linked to cuproptosis in diabetic retinopathy (DR), new pathobiological pathways and more accessible diagnostic markers can be developed.METHODS: The datasets related to DR were acquired from the Gene Expression Omnibus database, while genes associated with cuproptosis were sourced from previously published compilations. Consensus clustering was conducted to delineate distinct DR subclasses. Feature genes were identified utilizing weighted correlation network analysis (WGCNA). Additionally, two machine-learning algorithms were employed to refine the selection of feature genes. Finally, we conducted preliminary validation experiments to ascertain the involvement of cuproptosis in DR development and the transcriptional regulation of critical genes using both the streptozotocin-induced diabetic mouse model and the high glucose-induced BV2 model.
RESULTS: In the STZ-induced diabetic mouse retinas, a decrease in the expression of cuproptosis signature proteins (FDX1, DLAT, and NDUFS8) suggested the occurrence of cuproptosis in DR. Subsequently, the expression of eight cuproptosis differential genes was validated through the STZ-induced diabetes and oxygen-induced retinopathy (OIR) models, with the key gene SLC31A1 showing upregulation in both models and dataset species. Further analyses, including weighted gene co-expression network analysis, GSVA, and immune infiltration analysis, indicated a close correlation between cuproptosis and microglia function. Additionally, validation in an in vitro model of microglia indicated the occurrence of cuproptosis in microglia under high glucose conditions, alongside abnormal expression of STAT1 with SLC31A1.
CONCLUSION: Our findings suggest that STAT1/SLC31A1 may pave the way for a deeper comprehension of the mechanistic basis of DR and offer potential therapeutic avenues.

Keywords:  Bioinformatics analysis; Cuproptosis; Diabetic retinopathy; Microglia; STAT1-SLC31A1 axis

DOI:  https://doi.org/10.1016/j.gene.2024.148861
J Neuroimmunol. 2024 Aug 14. pii: S0165-5728(24)00152-8. [Epub ahead of print]395 578433

Microglial-mediated immune mechanisms in autoimmune uveitis: Elucidating pathogenic pathways and targeted therapeutics.

Monika Sharma, Pankaj Pal, Sukesh Kumar Gupta, Mrugendra B Potdar, Aarti V Belgamwar.

  This review offers a comprehensive examination of the role of microglia in the pathogenesis of autoimmune uveitis, an inflammatory eye disease with significant potential for vision impairment. Central to our discussion is the dual nature of microglial cells, which act as both protectors and potential perpetrators in the immune surveillance of the retina. We explore the mechanisms of microglial activation, highlighting the key signaling pathways involved, such as NF-κB, JAK/STAT, MAPK, and PI3K/Akt. The review also delves into the genetic and environmental factors influencing microglial behavior, underscoring their complex interaction in disease manifestation. Advanced imaging techniques and emerging biomarkers for microglial activation, pivotal in diagnosing and monitoring the disease, are critically assessed. Additionally, we discuss current and novel therapeutic strategies targeting microglial activity, emphasizing the shift towards more precise and personalized interventions. This article aims to provide a nuanced understanding of microglial dynamics in autoimmune uveitis, offering insights into potential avenues for effective treatment and management.

Keywords:  Autoimmune uveitis; Microglia; Microglial activation; Neuroinflammation; Ocular immunology; Signaling pathways

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578433
Mol Neurobiol. 2024 Aug 19.

Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury.

Yeyang Xian, Jie Liu, Mengxuan Dai, Wensheng Zhang, Minye He, Zhengnong Wei, Yutao Jiang, Shiyong Le, Zhuoang Lin, Shuai Tang, Yunfei Zhou, Liming Dong, Jinzheng Liang, Jie Zhang, Liang Wang.

  Reducing secondary injury is a key focus in the field of spinal cord injury (SCI). Recent studies have revealed the role of lymphangiogenesis in reducing secondary damage to central nerve. However, the mechanism of lymphangiogenesis is not yet clear. Macrophages have been shown to play an important role in peripheral tissue lymphangiogenesis. Microglia is believed to play a role similar to macrophages in the central nervous system (CNS); we hypothesized that there was a close relationship between microglia and central nerve system lymphangiogenesis. Herein, we used an in vivo model of SCI to explored the relationship between microglia and spinal cord lymphangiogenesis and further investigated the polarization of microglia and its role in promoting spinal cord lymphangiogenesis by a series of in vitro experiments. The current study elucidated for the first time the relationship between microglia and lymphangiogenesis around the spinal cord after SCI. Classical activated (M1) microglia can promote lymphangiogenesis by secreting VEGF-C which further increases polarization and secretion of lymphatic growth factor by activating VEGFR3. The VEGF-C/VEGFR3 pathway activation downregulates microglia autophagy, thereby regulating the microglia phenotype. These results indicate that M1 microglia promote lymphangiogenesis after SCI, and activated VEGF-C/VEGFR3 signaling promotes M1 microglia polarization by inhibiting autophagy, thereby facilitates lymphangiogenesis.

Keywords:  Autophagy; Lymphangiogenesis; Microglia; Spinal cord injury; VEGF-C

DOI:  https://doi.org/10.1007/s12035-024-04437-5