bims-microg 2025-01-05 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–01–05
nine papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia and Immune cells interactions in multiple sclerosis cognitive impairment: a postmortem study.
Microglia-like cells from patient monocytes demonstrate increased phagocytic activity in probable Alzheimer's disease.
ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.
Tgm2-Catalyzed Covalent Cross-Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia.
Thioredoxin-interacting protein (TXNIP) inhibition promotes retinal ganglion cell survival and facilitates M1-like microglial transformation via the PI3K/Akt pathway in glaucoma.
Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2.
SIRT2 Promotes NLRP3-Mediated Microglia Pyroptosis and Neuroinflammation via FOXO3a Pathway After Subarachnoid Hemorrhage.
The role of microglia in Neuroinflammation associated with cardiopulmonary bypass.
CLEC7A Knockdown Alleviates Ischemic Stroke by Inhibiting Pyroptosis and Microglia Activation.

J Neuroinflammation. 2024 Dec 31. 21(1): 332

Microglia and Immune cells interactions in multiple sclerosis cognitive impairment: a postmortem study.

Catarina Barros, Ainhoa Alberro, Adelaide Fernandes.

  Multiple Sclerosis (MS), a neuroinflammatory disease of the central nervous system, is one of the commonest causes of non-traumatic disability among young adults. Impaired cognition arises as an impactful symptom affecting more than 50% of the patients and with substantial impact on social, economic, and individual wellbeing. Despite the lack of therapeutic strategies, many efforts have been made to understand the mechanisms behind cognitive impairment in MS patients. Here, we aimed to investigate whether microglia-derived synaptic elimination and immune interactions are exacerbated in MS patients with impaired cognition when compared to non-demented controls (NDC) and cognitively preserved MS patients, that may clarify the role of immune cell interplay in MS cognitive deficits. Postmortem hippocampal samples were obtained from NDCs and MS patients. Sixteen MS patients were categorized based on their cognitive status: preserved cognition (MSCP) and impaired cognition (MSCI). Immunohistochemistry studies were conducted to explore the density of microglia, their role in synaptic engulfment, and their interaction with CD8+ immune cells in the context of cognitive impairment in MS. In high synaptic density hippocampal regions, MSCI patients exhibited a massive presence of microglia cells actively engulfing both excitatory and inhibitory synapses, accompanied by morphological alterations. Additionally, there was an increased expression of the complement protein C1q particularly localized at inhibitory synapses within microglia cells, suggesting a preferential engulfment of complement-tagged inhibitory synapses in MSCI patients. Furthermore, in hippocampal lesions of MSCI patients, we detected a significant infiltration of microglia and CD8 T cells that may be contributing to the smouldering MS and cognitive deterioration. These findings demonstrate that cognitive deficits occurring in MS are associated with microglia engulfment of C1q-tagged inhibitory synapses, which may be driven by direct or indirect stimulation from CD8+ T cells.

Keywords:  CD8 T cells; Cognitive impairment; Microglia; Multiple sclerosis; Synaptic pruning

DOI:  https://doi.org/10.1186/s12974-024-03326-x
Mol Cell Neurosci. 2024 Dec 27. pii: S1044-7431(24)00075-7. [Epub ahead of print]132 103990

Microglia-like cells from patient monocytes demonstrate increased phagocytic activity in probable Alzheimer's disease.

Ceren Perihan Gonul, Cagla Kiser, Emis Cansu Yaka, Didem Oz, Duygu Hunerli, Deniz Yerlikaya, Melis Olcum, Pembe Keskinoglu, Gorsev Yener, Sermin Genc.

  Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid plaques, phosphorylated tau tangles and microglia toxicity, resulting in neuronal death and cognitive decline. Since microglia are recognized as one of the key players in the disease, it is crucial to understand how microglia operate in disease conditions and incorporate them into models. The studies on human microglia functions are thought to reflect the post-symptomatic stage of the disease. Recently developed methods involve induced microglia-like cells (iMGs) generated from patients' blood monocytes or induced pluripotent stem cells (iPSCs) as an alternative to studying the microglia cells in vitro. In this research, we aimed to investigate the phenotype and inflammatory responses of iMGs from AD patients. Monocytes derived from blood using density gradient centrifugation were differentiated into iMGs using a cytokine cocktail, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). After differentiation, cells were assessed by morphological analysis and a microglia surface marker, TMEM119. We used stimulants, lipopolysaccharide (LPS) and beta-amyloid, to examine iMGs' functions. Results showed that iMGs derived from AD patients exhibited increased secretion of pro-inflammatory cytokines upon LPS stimulation. Furthermore, their phagocytic ability was also heightened in stimulated and unstimulated conditions, with cells derived from patients showing increased phagocytic activity compared to healthy controls. Overall, these findings suggest that iMGs derived from patients using the direct conversion method possess characteristics of human microglia, making them an easy and promising model for studying microglia function in AD.

Keywords:  Alzheimer's disease; Human peripheral blood cells; Induced microglia cells (iMG); Monocytes

DOI:  https://doi.org/10.1016/j.mcn.2024.103990
Front Immunol. 2024 ;15 1509370

ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.

Naixin Ren, Hutao Zhang, Tao Li, Huafang Ji, Zhen Zhang, He Wu.

  Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.

Keywords:  ATP5J; intracerebral hemorrhage; microglia; mitochondrial reprogramming; secondary brain injury

DOI:  https://doi.org/10.3389/fimmu.2024.1509370
Aging Cell. 2025 Jan 03. e14463

Tgm2-Catalyzed Covalent Cross-Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia.

Zhiqiang Li, Tianxiang Wang, Sijing Du, Zelong Miao, Yujiao Zhao, Yuxiang Tang, Xianbin Meng, Shangcheng Yu, Dongyuan Zhang, Hao Jiang, Kunlin Du, Wei Wei, Haiteng Deng.

  Microglia, as resident immune cells in the central nervous system (CNS), play a crucial role in maintaining homeostasis and phagocytosing metabolic waste in the brain. Senescent microglia exhibit decreased phagocytic capacity and increased neuroinflammation through senescence-associated secretory phenotype (SASP). This process contributes to the development of various neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we found that SASP was elevated in senescent microglia, and proteomics showed that Tgm2 was upregulated. Mechanistically, we revealed that Tgm2-catalyzed covalent cross-linking of IκBα at K22 and Q248 residues in the cytoplasm of microglia, resulting in the reduction of IκBα and nuclear translocation of NF-κB to promote SASP production. Treatment of senescent microglia with Tgm2 inhibitors (Tg2-IN1 and Cys-D) resulted in reduced NF-κB nuclear translocation and decreased SASP. Additionally, oral administration of Cys-D significantly improved the aging phenotype in aged mice. To summarize, Tgm2 is a potential target for antiaging, and inhibitors of Tgm2 can serve as novel prophylactics or senomorphics.

Keywords:  IκBα; NF‐κB; SASP; Tgm2; cross‐linking; senescent microglia; senomorphics

DOI:  https://doi.org/10.1111/acel.14463
Mol Med. 2024 Dec 30. 30(1): 283

Thioredoxin-interacting protein (TXNIP) inhibition promotes retinal ganglion cell survival and facilitates M1-like microglial transformation via the PI3K/Akt pathway in glaucoma.

Junjue Chen, Huimin Zhong, Bingqiao Shen, Huan Yu, Yang Zhang, Ruiqi Han, Ping Huang, Shouyue Huang, Yisheng Zhong.

   BACKGROUND: Glaucoma is a group of heterogeneous neurodegenerative diseases with abnormal energy metabolism and imbalanced neuroinflammation in the retina. Thioredoxin-interacting protein (TXNIP) is involved in glucose and lipid metabolism, and associated with oxidative stress and inflammation, however, not known whether to be involved in glaucoma neuropathy and its underlying mechanisms.
METHODS: To establish the chronic ocular hypertension (COH) mice model. Western blot, RT-PCR, immunofluorescence and F-VEP were used to detect neuroinflammation level, glial activation and RGCs survival in retina of wild type, TXNIP knockout and MCC950 treatment COH mice. Microglia high-pressure cultured model was constructed. Western blot, RT-PCR and immunofluorescence were used to investigate the proinflammatory cytokines secretion, glucose uptake and phenotype transformation in wild type, TXNIP knockout and overexpressed microglia combined with IL-17A treatment. Finally, we explored the possible underlying mechanisms using relevant pathway inhibitor interventions.
RESULTS: In this study, for the first time we reported that TXNIP expression was remarkably increased in experimental glaucomatous retina of chronic ocular hypertension (COH) mice, and it was mainly expressed in the ganglion cells layer (GCL). In addition, we found that ablation of TXNIP promoted retinal ganglion cells (RGCs) survival and alleviated visual function impairment in experimental glaucoma. Then, we explored the spatiotemporal consistency between glial activation and retinal inflammation levels in COH mice respectively with TXNIP-deficiency and under treatment of a thermo-containing protein domain 3 (NLRP3) inhibitor MCC950, and the results indicated that TXNIP probably mediated neuroinflammation in glaucomatous retina by activating microglia. Furthermore, upregulation of TXNIP was found in pressure-stimulated microglia, whereas silencing TXNIP facilitated microglial polarization trending towards M1 type and reduced glucose transporter-1 (Glut-1) expression on microglia under high pressure in vitro. Moreover, IL-17A was found to play a role in acting synergistically with TXNIP upon the regulation of microglia polarity transformation. Finally, knockout of TXNIP was revealed to promote PI3K phosphorylation, whereas inhibition of PI3K by LY294002 effectively suppressed Glut-1 expression, glucose uptake, and M1-like transformation tendency in microglia obtained from TXNIP-deficiency mice under high pressure stimulation.
CONCLUSIONS: TXNIP is significantly involved in the inflammation-related neuropathy of experimental glaucoma and probably facilitates M1-like microglial transformation via PI3K/Akt pathway.

Keywords:  Energy metabolism; Experimental glaucoma; Microglia; Neuroinflammation; PI3K/AKT; TXNIP

DOI:  https://doi.org/10.1186/s10020-024-01058-5
Ecotoxicol Environ Saf. 2024 Dec 27. pii: S0147-6513(24)01696-8. [Epub ahead of print]290 117620

Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2.

Siyao Li, Mingdan You, Chengjie Chen, Jingqi Fu, Yuanyuan Xu, Jingbo Pi, Yi Wang.

  Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic structures. Nrf2 is deeply implicated in the status of microglial activation; therefore, we also investigated whether it is involved in the above process. Nrf2 knockout mice and wild-type mice were used to explore prolonged Cd exposure-induced synaptic damages, learning-memory impairments, and microglial activation. We also created Nrf2 knockdown (KD) BV2 microglia to investigate the role of cell-specific Nrf2 in Cd-induced microglial activation. Finally, we developed co-culture systems of either Nrf2-KD or Scramble microglia and primary neurons or HT22 neurons to study the effects of Nrf2-regulated microglial activation on synaptic damages induced by Cd. Moreover, the direct engulfment, a main avenue in microglia that may be responsible for Cd-induced synaptic damages and regulated by Nrf2, was specifically studied in vivo and in vitro, along with underlying specific mechanisms. We found that Cd exposure induced microglial overactivation, and Cd-overactivated microglia impaired synapses through direct engulfment of synaptic structures, which may contribute to learning-memory impairments. Both fractalkine and complement pathways underlay microglial engulfment of synapses due to Cd exposure. Nrf2 was essential in preventing microglial overactivation and subsequent direct engulfment, thus preventing the consequent synaptic damages due to Cd exposure. Overall, the findings suggest that Cd-overactivated microglia damage synapses through direct engulfment, resulting from the activation of fractalkine and complement pathways.

Keywords:  Cadmium; Direct engulfment; Microglia; Nrf2; Synapses

DOI:  https://doi.org/10.1016/j.ecoenv.2024.117620
J Inflamm Res. 2024 ;17 11679-11698

SIRT2 Promotes NLRP3-Mediated Microglia Pyroptosis and Neuroinflammation via FOXO3a Pathway After Subarachnoid Hemorrhage.

Jia-Qing Sun, Bin Sheng, Sen Gao, Xun-Zhi Liu, Yue Cui, Zheng Peng, Xiang-Xin Chen, Peng-Fei Ding, Zong Zhuang, Ling-Yun Wu, Chun-Hua Hang, Wei Li.

   Purpose: This study primarily elucidating the specific mechanism of SIRT2 on neuroinflammation and microglial pyroptosis in a mouse model of SAH.
Patients and Methods: CSF were collected from 57 SAH patients and 11 healthy individuals. C57BL/6 mouse SAH model was established using prechiasmatic cistern blood injection and the in vitro hemoglobin (Hb) stimulation microglia model. Lentivirus was used as a vector for RNA interference technology to knock down the SIRT2 gene expression. Small interfering RNA was used to knockdown the expression of FOXO3a. The tools included measurements of brain water content, neurological scores, Western blot, PCR, ELISA, TEM, immunofluorescence, LDH assay, modified Garcia score, and balance beam tests to evaluate changes in pyroptosis and neuroinflammatory responses.
Results: In CSF samples from SAH patients, elevated levels of SIRT2 and GSDMD were observed, with SIRT2 demonstrating particular diagnostic value for predicting prognosis at the 3-month follow-up. SIRT2 upregulation exacerbated neurological deficits, brain edema, and blood-brain barrier disruption in mice following SAH. SIRT2 increased GSDMD, caspase-1, and IL-1β/IL-18 expression, and amplified GSDMD-positive microglia. FOXO3a was also upregulated post-SAH. siRNA-mediated SIRT2 knockdown ameliorated microglial pyroptosis after SAH. FOXO3a siRNA reduced NLRP3 inflammasome activation and microglial pyroptosis severity, along with neuroinflammation post-SAH.
Conclusion: In summary, SIRT2 promoted microglial pyroptosis, primarily by increasing the expression and activity of Foxo3a, thereby exacerbating neuroinflammatory damage following subarachnoid hemorrhage.

Keywords:  FOXO3a; GSDMD; SIRT2; microglial pyroptosis; subarachnoid hemorrhage

DOI:  https://doi.org/10.2147/JIR.S487716
Front Cell Neurosci. 2024 ;18 1496520

The role of microglia in Neuroinflammation associated with cardiopulmonary bypass.

Lingda Meng, Tianxiang Gu, Peng Yu, Zhiwei Zhang, Zhijing Wei.

  Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are indispensable core techniques in cardiac surgery. Numerous studies have shown that cardiopulmonary bypass and deep hypothermic circulatory arrest are associated with the occurrence of neuroinflammation, accompanied by the activation of microglia. Microglia, as macrophages in the central nervous system, play an irreplaceable role in neuroinflammation. Current research on neuroinflammation induced by microglia activation mainly focuses on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, neuropathic pain, acquired brain injury, and others. However, there is relatively limited research on microglia and neuroinflammation under conditions of cardiopulmonary bypass and deep hypothermic circulatory arrest. The close relationship between cardiopulmonary bypass, deep hypothermic circulatory arrest, and cardiac surgery underscores the importance of identifying targets for intervening in neuroinflammation through microglia. This could greatly benefit cardiac surgery patients during cardiopulmonary bypass and the perioperative period, significantly improving patient prognosis. This review article provides the first comprehensive discussion on the signaling pathways associated with neuroinflammation triggered by microglia activation, the impact of cardiopulmonary bypass on microglia, as well as the current status and advancements in cardiopulmonary bypass animal models. It provides new insights and methods for the treatment of neuroinflammation related to cardiopulmonary bypass and deep hypothermic circulatory arrest, holding significant importance for clinical treatment by cardiac surgeons, management strategies by cardiopulmonary bypass physicians, and the development of neurologically related medications.

Keywords:  cardiopulmonary bypass; deep hypothermic circulatory arrest; microglia; neuroinflammation; signaling pathways

DOI:  https://doi.org/10.3389/fncel.2024.1496520
J Integr Neurosci. 2024 Dec 23. 23(12): 219

CLEC7A Knockdown Alleviates Ischemic Stroke by Inhibiting Pyroptosis and Microglia Activation.

Wei Li, Xiaoli Feng, Manyu Zhang, Kangmeng Wang, Kailai Huang, Zhenqiang Zhao, Min Xia.

   BACKGROUND: Ischemic stroke (IS) is the leading cause of mortality worldwide. Herein, we aimed to identify novel biomarkers and explore the role of C-type lectin domain family 7 member A (CLEC7A) in IS.
METHODS: Differentially expressed genes (DEGs) were screened using the GSE106680, GSE97537, and GSE61616 datasets, and hub genes were identified through construction of protein-protein interaction networks. An IS model was established by middle cerebral artery occlusion and reperfusion (MCAO/R). Neural function was assessed using triphenyl tetrazolium chloride, hematoxylin-eosin, and terminal deoxynucleotidyl transferase-mediated nick-end labeling. A cell counting kit was used to detect cell viability following oxygen-glucose deprivation/reperfusion (OGD/R). Inflammatory factors were detected using enzyme-linked immunosorbent assay. The mRNA and protein expression levels were detected using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively.
RESULTS: Fc fragment of Immunoglobulin G (IgG) receptor IIIa (FCGR3A), Fc fragment of Immunoglobulin E (IgE) receptor Ig (FCER1G), Complement component 5a receptor 1 (C5AR1), CLEC7A, Plasminogen activator, urokinase (PLAU), and C-C motif chemokine ligand 6 (CCL6) were identified as important hub genes, from which CLEC7A was selected as the primary subject of this study. The activation of microglia and pyroptosis were observed in MCAO/R model with increased levels of interleukin (IL)-1β, IL-18, tumor necrosis factor-α, and lactate dehydrogenase. CLEC7A knockdown was found to promote cell viability in BV2 cells and inhibiting pyroptosis in HT22 cells. CLEC7A knockdown in microglia also decreased infarct volume and neurological deficit scores, and alleviated injury and neuronal apoptosis in IS rats. CLEC7A knockdown inhibited pyroptosis and microglial activation in the MCAO/R model. A pyroptosis activator reversed the effect of CLEC7A knockdown on the viability of OGD/R-treated HT22 cells.
CONCLUSION: CLEC7A is a promising biomarker of IS. CLEC7A knockdown alleviates IS by inhibiting pyroptosis and microglial activation.

Keywords:  CLEC7A; differential expression genes; ischemic stroke; microglia; pyroptosis

DOI:  https://doi.org/10.31083/j.jin2312219