bims-microg 2024-11-24 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–11–24
27 papers selected by
Marcus Karlstetter, Universität zu Köln

BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis.
Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39.
Silencing of circular RNA PTP4A2 ameliorates depressive-like behaviors by inhibiting microglia activation in mice.
Angiotensin-II drives changes in microglia-vascular interactions in rats with heart failure.
Subretinal microglia support donor photoreceptor survival in rd1 mice.
Microglia-derived ADAM9 promote GHRH neurons pyroptosis by Mad2L2-JNK-caspase-1 pathway in subarachnoid hemorrhage.
Fueling neurodegeneration: metabolic insights into microglia functions.
Leveraging Single-Cell RNA-Seq to Generate Robust Microglia Aging Clocks.
ANGPTL4-mediated microglial lipid droplet accumulation: Bridging Alzheimer's disease and obesity.
Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation.
Retinal microglia-derived S100A9 incite NLRP3 inflammasome in a Western diet fed Ossabaw pig retina.
Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model.
Effects of electroacupuncture on microglia phenotype and epigenetic modulation of C/EBPβ in SAMP8 mice.
Magnetic field in the extreme low frequency band protects neuronal and microglia cells from oxygen-glucose deprivation.
HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.
Microglia induce an interferon-stimulated gene expression profile in glioblastoma and increase glioblastoma resistance to temozolomide.
Microglia in the spinal cord stem cell niche regulate neural precursor cell proliferation via soluble CD40 in response to myelin basic protein.
Inhibition of iron-induced cofilin activation and inflammation in microglia by a novel cofilin inhibitor.
Pharmacological depletion of microglia protects against alcohol-induced corticolimbic neurodegeneration during intoxication in male rats.
High-density lipoprotein alleviates ocular inflammation by downregulating M1 microglia and pyroptosis through regulating lipid accumulation and Caveolin-1 expression.
Outward depolarization of the microglia mitochondrial membrane potential following lipopolysaccharide exposure: a novel screening tool for microglia metabolomics.
Microglial Lyzl4 Facilitates β-Amyloid Clearance in Alzheimer's Disease.
Residual microglia following short-term PLX5622 treatment in 5xFAD mice exhibit diminished NLRP3 inflammasome and mTOR signaling, and enhanced autophagy.
Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension.
TIA1 Mediates Divergent Inflammatory Responses to Tauopathy in Microglia and Macrophages.
Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation.
Aβ1-42 promotes microglial activation and apoptosis in the progression of AD by binding to TLR4.

Nat Commun. 2024 Nov 22. 15(1): 10116

BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis.

Ross C Gruber, Gregory S Wirak, Anna S Blazier, Lan Lee, Michael R Dufault, Nellwyn Hagan, Nathalie Chretien, Michael LaMorte, Timothy R Hammond, Agnes Cheong, Sean K Ryan, Andrew Macklin, Mindy Zhang, Nilesh Pande, Evis Havari, Timothy J Turner, Anthony Chomyk, Emilie Christie, Bruce D Trapp, Dimitry Ofengeim.

Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton's tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

DOI: https://doi.org/10.1038/s41467-024-54430-8
bioRxiv. 2024 Nov 05. pii: 2024.11.05.622122. [Epub ahead of print]

Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39.

Zhongxiao Fu, Mallikarjunarao Ganesana, Philip Hwang, Xiao Tan, Melissa Marie Kinkaid, Yu-Yo Sun, Emily Bian, Aden Weybright, Katia Sol-Church, Ukpong B Eyo, Clare Pridans, Francisco J Quintana, Simon C Robson, Pankaj Kumar, B Jill Venton, Anne Schaefer, Chia-Yi Kuan.

Microglia and the border-associated macrophages (BAMs) contribute to the modulation of cerebral blood flow (CBF), but the mechanisms have remained ill-defined. Here, we show that microglia regulate the CBF baseline and upsurges after whisker stimulation or intracisternal magna injection of adenosine triphosphate (ATP). Genetic or pharmacological depletion of microglia reduces the activity-dependent hyperemia but not the cerebrovascular responses to adenosine stimulation. Notably, microglia repopulation corrects these CBF reactivity deficits. The microglial-dependent regulation of CBF requires the ATP-sensing P2ry12 receptor and the ectonucleotidase CD39 that initiates the breakdown of extracellular ATP. Pharmacological inhibition or microglia-specific deletion of CD39 simulates the CBF anomalies detected in microglia-deficient mice and reduces the rise of extracellular adenosine after whisker stimulation. Together, these results suggest that the microglial CD39-initiated conversion of extracellular ATP to adenosine is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.

DOI: https://doi.org/10.1101/2024.11.05.622122
J Neuroimmunol. 2024 Nov 13. pii: S0165-5728(24)00205-4. [Epub ahead of print]397 578486

Silencing of circular RNA PTP4A2 ameliorates depressive-like behaviors by inhibiting microglia activation in mice.

Han Zhang, Xiang Chen, Jialu Qian.

  Major depressive disorder (MDD) is a prevalent mental illness and showed a strong link with inflammation. Microglia, as the main resident immune cells, play an important role in the occurrence and development of depression. Circular RNA PTP4A2 (circPTP4A2) was highly expressed in microglia inflammation induced by oxygen glucose deprivation/reperfusion. However, whether circPTP4A2 involves in microglia inflammation in MDD is not clear. Here, chronic unpredictable stress (CUS) induced depressive behaviors and microglia activation in mouse hippocampus, accompanied by the elevated expression of circPTP4A2. Knockdown circPTP4A2 in mouse hippocampus ameliorated depressive-like behaviors and microglia activation. Moreover, CUS promoted phosphorylation of ERK, JNK and P38 in mouse hippocampus as same as LPS-exposed BV2 microglia. Only P38 phosphorylation was inhibited by circPTP4A2 knockdown in the hippocampus. P38 inhibitor, sb203580, repressed circPTP4A2 overexpression-induced inflammatory reaction in BV2 cells. These findings suggest that circPTP4A2 promotes depressive-like behaviors and microglia activation via P38 phosphorylation.

Keywords:  CircPTP4A2; Inflammation; Major depressive disorder; Microglia activation; P38 phosphorylation

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578486
Commun Biol. 2024 Nov 19. 7(1): 1537

Angiotensin-II drives changes in microglia-vascular interactions in rats with heart failure.

Ferdinand Althammer, Ranjan K Roy, Matthew K Kirchner, Yuval Podpecan, Jemima Helen, Shaina McGrath, Elba Campos Lira, Javier E Stern.

Activation of microglia, the resident immune cells of the central nervous system, leading to the subsequent release of pro-inflammatory cytokines, has been linked to cardiac remodeling, autonomic disbalance, and cognitive deficits in heart failure (HF). While previous studies emphasized the role of hippocampal Angiotensin II (AngII) signaling in HF-induced microglial activation, unanswered mechanistic questions persist. Evidence suggests significant interactions between microglia and local microvasculature, potentially affecting blood-brain barrier integrity and cerebral blood flow regulation. Still, whether the microglial-vascular interface is affected in the brain during HF remains unknown. Using a well-established ischemic HF rat model, we demonstrate the increased abundance of vessel-associated microglia (VAM) in HF rat hippocampi, along with an increased expression of AngII AT1a receptors. Acute AngII administration to sham rats induced microglia recruitment to brain capillaries, along with increased expression of TNFα. Conversely, administering an AT1aR blocker to HF rats prevented the recruitment of microglia to blood vessels, normalizing their levels to those in healthy rats. These results highlight the critical importance of a rather understudied phenomenon (i.e., microglia-vascular interactions in the brain) in the context of the pathophysiology of a highly prevalent cardiovascular disease, and unveil novel potential therapeutic avenues aimed at mitigating neuroinflammation in cardiovascular diseases.

DOI: https://doi.org/10.1038/s42003-024-07229-8
Stem Cell Res Ther. 2024 Nov 19. 15(1): 436

Subretinal microglia support donor photoreceptor survival in rd1 mice.

Qinjia Ren, Fang Lu, Ruwa Hao, Yingying Chen, Chen Liang.

   PURPOSE: To investigate the potential relationship between subretinal microglia and transplanted donor photoreceptors.
METHODS: Photoreceptor precursors were transplanted into wild-type mice and rd1 mice by trans-scleral injection. Immunohistochemistry was employed to detect microglia and macrophages. PlX5622 feed was used to achieve microglia depletion and microglia repopulation. RNA-seq and qPCR were utilized to evaluate gene expression. Confocal microscopy was used to observe the interaction between microglia and donor photoreceptors.
RESULTS: Donor photoreceptors survived in rd1 mice but not in wild-type mice after trans-scleral injection. The microglial cells closely interacted with donor cells. While donor cells failed to survive in rd1 mice after microglia depletion, they could survive following microglia repopulation. The RNA-seq analysis showed a pro-neurodevelopmental effect of sub-retinal microglia/RPE tissue in rd1 mice.
CONCLUSIONS: Subretinal microglia supported donor photoreceptor survival in rd1 mice.

Keywords:  Inherited retinal degeneration; Photoreceptor transplantation; Subretinal microglia

DOI:  https://doi.org/10.1186/s13287-024-04052-0
J Neuroinflammation. 2024 Nov 19. 21(1): 302

Microglia-derived ADAM9 promote GHRH neurons pyroptosis by Mad2L2-JNK-caspase-1 pathway in subarachnoid hemorrhage.

Jian Mao, Yun Bao, Fan Liu, Qiyun Ye, Junxiang Peng, Jing Nie, Lijun Huang, Yonghong Liao, Yiheng Xing, Dongyang Wu, Ke Wang, Wenfeng Feng, Songtao Qi, Jun Pan, Binghui Qiu.

  The incidence of growth hormone deficiency (GHD) after subarachnoid hemorrhage (SAH) is significantly higher than that of other neuroendocrine disorders, but the mechanism is still elusive. We used mass spectrometry to identify differentially expressed proteins in cerebrospinal fluid samples from a well-characterized cohort of patients. A total of 683 proteins were identified, including 39 upregulated proteins in the GHD group. ADAM9 was most highly associated with GHD. In vivo, ADAM9 colocalized with M1 microglia markers, GH and cognitive ability of mice decreased significantly, and microglia secreted ADAM9 significantly. ADAM9 regulates pyroptosis of GHRH neurons by the Mad2L2-JNK-caspase-1 pathway. Sorafenib inhibits ADAM9 secretion by microglia and improves GH levels and the cognitive ability of mice. This study found that the crosstalk between GHRH neurons and neuroglial cells in the hypothalamic arcuate nucleus, i.e., microglia, is an essential factor in the formation of GHD in SAH. We propose that neutralization of ADAM9 production by microglia might be a potential therapy for GHD after SAH.

Keywords:  ADAM9; GHRH neuron; Microglia; Pyroptosis; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1186/s12974-024-03299-x
J Neuroinflammation. 2024 Nov 17. 21(1): 300

Fueling neurodegeneration: metabolic insights into microglia functions.

Mohammadamin Sadeghdoust, Aysika Das, Deepak Kumar Kaushik.

  Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Keywords:  Immunometabolism; Microglia; Neurodegenerative diseases; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12974-024-03296-0
bioRxiv. 2024 Nov 07. pii: 2024.10.05.616811. [Epub ahead of print]

Leveraging Single-Cell RNA-Seq to Generate Robust Microglia Aging Clocks.

Natalie Stanley, Luvna Dhawka, Sneha Jaikumar, Yu-Chen Huang, Anthony S Zannas.

  'Biological aging clocks' - composite molecular markers thought to capture an individual's biological age - have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets, we develop and compare computational approaches for generating transcriptome-wide summaries to establish robust microglia aging clocks. Our results reveal that unsupervised, frequency-based featurization approaches strike a balance in accuracy, interpretability, and computational efficiency. We further extrapolate and demonstrate applicability of such microglia clocks to readily available bulk RNA-seq data with environmental inputs. Single-cell-derived clocks can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.

Keywords:  aging clocks; microglia; neuroimmunology; single-cell

DOI:  https://doi.org/10.1101/2024.10.05.616811
Neurobiol Dis. 2024 Nov 20. pii: S0969-9961(24)00343-7. [Epub ahead of print] 106741

ANGPTL4-mediated microglial lipid droplet accumulation: Bridging Alzheimer's disease and obesity.

Nan Li, Xiaojun Wang, Ruilang Lin, Fuxia Yang, Hung-Chen Chang, Xuchao Gu, Jun Shu, Guidong Liu, Yongfu Yu, Wenshi Wei, Zhijun Bao.

  Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD. RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity. In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD.

Keywords:  ANGPTL4; Aging; Alzheimer's disease; Microglia; Obesity

DOI:  https://doi.org/10.1016/j.nbd.2024.106741
J Neurosci. 2024 Nov 18. pii: e2027232024. [Epub ahead of print]

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation.

Zhefu Que, Maria I Olivero-Acosta, Morgan Robinson, Ian Chen, Jingliang Zhang, Kyle Wettschurack, Jiaxiang Wu, Tiange Xiao, C Max Otterbacher, Vinayak Shankar, Hope Harlow, Seoyong Hong, Benjamin Zirkle, Muhan Wang, Ningren Cui, Purba Mandal, Xiaoling Chen, Brody Deming, Manasi Halurkar, Yuanrui Zhao, Jean-Christophe Rochet, Ranjie Xu, Amy L Brewster, Long-Jun Wu, Chongli Yuan, William C Skarnes, Yang Yang.

Neuronal hyperexcitability is a hallmark of epilepsy. It has been recently shown in rodent models of seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interact with human neurons to regulate hyperexcitability mediated by an epilepsy-causing genetic mutation found in patients is unknown. The SCN2A gene is responsible for encoding the voltage-gated sodium channel Nav1.2, one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation leads to hyperexcitability in a male donor (KOLF2.1) hiPSC-derived cortical neuron model. Microglia originate from a different lineage (yolk sac) and are not naturally present in hiPSCs-derived neuronal cultures. To study how microglia respond to neurons carrying a disease-causing mutation and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display increased branch length and enhanced process-specific calcium signal when co-cultured with Nav1.2-L1342P neurons. Moreover, the presence of microglia significantly lowered the repetitive action potential firing and current density of sodium channels in neurons carrying the mutation. Additionally, we showed that co-culturing with microglia led to a reduction in sodium channel expression within the axon initial segment of Nav1.2-L1342P neurons. Furthermore, we demonstrated that Nav1.2-L1342P neurons release a higher amount of glutamate compared to control neurons. Our work thus reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation.Significance Statement Seizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

DOI: https://doi.org/10.1523/JNEUROSCI.2027-23.2024
bioRxiv. 2024 Oct 31. pii: 2024.10.30.621160. [Epub ahead of print]

Retinal microglia-derived S100A9 incite NLRP3 inflammasome in a Western diet fed Ossabaw pig retina.

Rayne R Lim, Anju Thomas, Aparna Ramasubramanian, Shyam S Chaurasia.

Purpose: We established S100A9 as a myeloid-derived damage-associated molecular pattern (DAMPs) protein associated with increasing severity of diabetic retinopathy (DR) in type 2 diabetic subjects. The present study investigates the retinal localization, expression, and mechanisms of action for S100A9 in the young obese Ossabaw pig retina.
Methods: Retinae from Ossabaw pigs fed a Western diet for 10 weeks were evaluated for S100 and inflammatory mediator expression using quantitative PCR and Western blot. Double immunohistochemistry was performed to identify the cellular sources of S100A9 in the pig retina. Primary pig retinal microglial cells (pMicroglia) were examined for S100A9 production. S100A9-induced responses were also investigated, and inhibitor studies elucidated the mechanism of action via the NLRP3 inflammasome. A specific inhibitor, Paquinimod (ABR-215757), was administered in vitro to assess the rescue of S100A9-induced NLRP3 inflammasome activation in pMicroglia.
Results: The expression of the S100 family in the obese Ossabaw pig retina showed a significant elevation of S100A9, consistent with increased levels of circulating S100A9. Moreover, the retina had elevated levels of inflammatory mediators IL-6, IL-8, MCP-1, IL-1β and NLRP3. Retinal microglia in obese Ossabaw were activated and accompanied by an increased expression of intracellular S100A9. pMicroglia isolated from pig retina transformed from ramified to amoeboid state when activated with LPS and produced high S100A9 transcript and protein levels. The S100A9 protein, in turn, further activated pMicroglia by heightened production of S100A9 transcripts and secretion of pro-inflammatory IL-1β protein. Inhibition of TLR4 with TAK242 and NLRP3 with MCC950 attenuated the production of IL-1β during S100A9 stimulus. Finally, pre-treatment with Paquinimod successfully reduced S100A9-driven increases of glycosylated-TLR4, NLRP3, ASC, Caspase-1, and IL-1β production.
Conclusion: We demonstrated that microglial-derived S100A9 perpetuates pro-inflammatory responses via the NLRP3 inflammasome in the retina of young Western-diet-fed Ossabaw pigs exhibiting diabetic retinopathy.

DOI: https://doi.org/10.1101/2024.10.30.621160
CNS Neurosci Ther. 2024 Nov;30(11): e70111

Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model.

Ran Sun, Tengyun Ma, Zheng Zhao, Yan Gao, Juan Feng, Xue Yang.

   AIMS: Remyelination is an endogenous repair process that is often deficient in multiple sclerosis (MS). Stimulation of remyelination is thought to help limit the progression of MS. This study aimed to investigate the expression pattern and function of a microglial phagocytosis-related gene, phospholipase D family member 4 (PLD4), in a cuprizone (CPZ)-induced MS mouse model.
METHODS: The extent of remyelination was assessed using LFB staining. Myelin phagocytosis assay was used to investigate the effect of Pld4 on microglial phagocytic activity.
RESULTS: Pld4 was upregulated in the corpus callosum during demyelination and remyelination. AAV9-mediated Pld4 deficiency impaired remyelination and reduced the number of Olig2-positive cells. In the corpus callosum of Pld4-deficient mice, the microglial phagocytosis marker MAC2 was reduced, accompanied by inhibition of TrkA/AKT signaling. Similarly, the phagocytosis assay showed that Pld4 knockdown significantly inhibited myelin debris phagocytosis by BV2 cells. The AKT activator SC79 reversed the Pld4 deficiency-induced inhibition of microglial phagocytic activity and rescued the impaired remyelination in Pld4-deficient mice.
CONCLUSION: PLD4 is upregulated in CPZ-induced MS and modulates microglial phagocytosis and remyelination via the AKT pathway. Our findings provide experimental evidence for a better understanding of the molecular mechanism of MS.

Keywords:  AKT; cuprizone; multiple sclerosis; phagocytosis; phospholipase D family member 4; remyelination

DOI:  https://doi.org/10.1111/cns.70111
Brain Res. 2024 Nov 20. pii: S0006-8993(24)00594-8. [Epub ahead of print] 149339

Effects of electroacupuncture on microglia phenotype and epigenetic modulation of C/EBPβ in SAMP8 mice.

Li Wang, Weixian Li, Wenhui Wu, Qing Liu, Min You, Xinyuan Liu, Cheng Ye, Jiangmin Chen, Qian Tan, Guangya Liu, Yanjun Du.

BACKGROUD: Alzheimer's disease (AD), an age-progressive neurodegenerative disease, is featured by a relentless deterioration of cognitive abilities. In parallel with the hypotheses of Aβ and tau, microglia-mediated neuroinflammation is a core pathological hallmark of AD. Promoting the transition of microglia from M1 to M2 phenotype and inhibition of neuroinflammatory response provide new insights into the treatment of AD. And substantial studies have confirmed that overexpression of C/EBPβ accelerates the progression of AD pathology. Acupuncture is renowned for its unique advantages including safety and effectiveness, which has gained wide application in geriatric diseases, and thoroughly exploring the mechanism for its treatment of AD will provide scientific basis for its clinical application.
METHODS: In this study, SAMP8 mice were employed and EA therapy was performed as the main intervention. The combination of behavioural experiments (including water maze and novel objective recognition), Immunofluorescence, Western blot, and Chip-qPCR assay were performed to compare between different groups.
RESULTS: EA therapy facilitates the polarization of microglia from M1 to M2 phenotype, reduces pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and promotes the expression of anti-inflammatory factors (IL-4 and IL-10), as well as attenuates neuroinflammation. Simultaneously, EA also inhibits the enrichment of H3K9ac at C/EBPβ promoter region and expression of C/EBPβ. Thus, it was evident that EA had a favorable effect on ameliorating cognitive decline in SAMP8 mice.
CONCLUSION: EA therapy may ameliorate cognitive deficits in AD via facilitating microglia shift from M1 to M2 phenotype and epigenetically regulating C/EBPβ. And further studies are required to better understand how the mechanisms between microglia and epigenetic modulation of C/EBPβ are effective in reversing AD.

DOI: https://doi.org/10.1016/j.brainres.2024.149339
Front Cell Neurosci. 2024 ;18 1455158

Magnetic field in the extreme low frequency band protects neuronal and microglia cells from oxygen-glucose deprivation.

Paloma Mata, Stefano Calovi, Kami Pars Benli, Leyre Iglesias, María Isabel Hernández, Abraham Martín, Alberto Pérez-Samartín, Ander Ramos-Murguialday, María Domercq, Iñaki Ortego-Isasa.

  Ischemic stroke consists of rapid neural death as a consequence of brain vessel obstruction, followed by damage to the neighboring tissue known as ischemic penumbra. The cerebral tissue in the core of the lesions becomes irreversibly damaged, however, the ischemic penumbra is potentially recoverable during the initial phases after the stroke. Therefore, there is real need for emerging therapeutic strategies to reduce ischemic damage and its spread to the penumbral region. For this reason, we tested the effect of Extreme Low Frequency Electromagnetic Stimulation (ELF-EMS) on in vitro primary neuronal and microglial cultures under oxygen-glucose deprivation (OGD) conditions. ELF-EMS under basal non-OGD conditions did not induce any effect in cell survival. However, ELF-EMS significantly reduced neuronal cell death in OGD conditions and reduced ischemic induced Ca2+ overload. Likewise, ELF-EMS modulated microglia activation and OGD-induced microglia cell death. Hence, this study suggests potential benefits in the application of ELF-EMS to limit ischemic irreversible damages under in vitro stroke conditions, encouraging in vivo preclinical validations of ELF-EMS as a potential therapeutic strategy for ischemic stroke.

Keywords:  cell viability; extreme low frequency electromagnetic stimulation (ELF-EMS); microglia; neuron; oxygen and glucose deprivation; stroke

DOI:  https://doi.org/10.3389/fncel.2024.1455158
Microbes Infect. 2024 Nov 20. pii: S1286-4579(24)00202-8. [Epub ahead of print] 105460

HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.

Laura Reiche, Benedikt Plaack, Maike Lehmkuhl, Vivien Weyers, Joel Gruchot, Daniel Picard, Hervé Perron, Marc Remke, Christiane Knobbe-Thomsen, Guido Reifenberger, Patrick Küry, David Kremer.

  Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.

Keywords:  glioblastoma; glioma; human endogenous retrovirus type-W envelope protein; microglia; tumor microenvironment

DOI:  https://doi.org/10.1016/j.micinf.2024.105460
Neuropathol Appl Neurobiol. 2024 Dec;50(6): e13016

Microglia induce an interferon-stimulated gene expression profile in glioblastoma and increase glioblastoma resistance to temozolomide.

Mia Dahl Sørensen, Rikke Frydendahl Sick Olsen, Mark Burton, Stephanie Kavan, Stine Asferg Petterson, Mads Thomassen, Torben Arvid Kruse, Morten Meyer, Bjarne Winther Kristensen.

   AIMS: Glioblastoma is the most malignant primary brain tumour. Even with standard treatment comprising surgery followed by radiation and concomitant temozolomide (TMZ) chemotherapy, glioblastoma remains incurable. Almost all patients with glioblastoma relapse owing to various intrinsic and extrinsic resistance mechanisms of the tumour cells. Glioblastomas are densely infiltrated with tumour-associated microglia and macrophages (TAMs). These immune cells affect the tumour cells in experimental studies and are associated with poor patient survival in clinical studies. The aim of the study was to investigate the impact of microglia on glioblastoma chemo-resistance.
METHODS: We co-cultured patient-derived glioblastoma spheroids with microglia at different TMZ concentrations and analysed cell death. In addition, we used RNA sequencing to explore differentially expressed genes after co-culture. Immunostaining was used for validation.
RESULTS: Co-culture experiments showed that microglia significantly increased TMZ resistance in glioblastoma cells. RNA sequencing revealed upregulation of a clear interferon-stimulated gene (ISG) expression signature in the glioblastoma cells after co-culture with microglia, including genes such as IFI6, IFI27, BST2, MX1 and STAT1. This ISG expression signature is linked to STAT1 signalling, which was confirmed by immunostaining. The ISG expression profile observed in glioblastoma cells with enhanced TMZ resistance corresponded to the interferon-related DNA damage resistance signature (IRDS) described in different solid cancers.
CONCLUSIONS: Here, we show that the IRDS signature, linked to chemo-resistance in other cancers, can be induced in glioblastoma by microglia. ISG genes and the microglia inducing the ISG expression could be promising novel therapeutic targets in glioblastoma.

Keywords:  STAT; chemo‐resistance; glioblastoma; interferon; microglia

DOI:  https://doi.org/10.1111/nan.13016
Stem Cells. 2024 Nov 16. pii: sxae076. [Epub ahead of print]

Microglia in the spinal cord stem cell niche regulate neural precursor cell proliferation via soluble CD40 in response to myelin basic protein.

Nishanth Lakshman, Filip Stojic, Cindi M Morshead.

  Neural stem cells (NSCs) are found along the neuraxis of the developing and mature central nervous system. They are found in defined niches that have been shown to regulate NSC behaviour in a regionally distinct manner. Specifically, previous research has shown that myelin basic protein (MBP), when presented in the spinal cord niche, inhibits NSC proliferation and oligodendrogenesis. Herein, we investigate the cell-based mechanism(s) underlying this spinal-cord niche derived MBP-mediated inhibition. We used reporter mice to sort for subpopulations of cells and found that spinal cord niche derived microglia release a soluble factor in response to MBP that is responsible for NSC inhibition. Microglia, but not other niche cells, release soluble CD40/TNFRSF5 (sCD40) in the presence of MBP which may indirectly reduce activation of transmembrane CD40/TNFRSF5 receptor on both spinal cord and brain NSCs. This is consistent with sCD40 binding to CD40 ligand (CD40L) thereby preventing CD40 receptor binding on NSCs and inhibiting NSC proliferation. The identification of the cell-based mechanism that regulates NSC behaviour in response to MBP, which is dysregulated in injury/disease, provides insight into a potential target for strategies to enhance neural repair through endogenous stem cell activation.

Keywords:  microglia; myelin basic protein; neural stem cells; spinal cord; stem cell niche

DOI:  https://doi.org/10.1093/stmcls/sxae076
J Neurochem. 2024 Nov 18.

Inhibition of iron-induced cofilin activation and inflammation in microglia by a novel cofilin inhibitor.

Faheem Shehjar, Antonisamy William James, Reetika Mahajan, Zahoor A Shah.

  Neuroinflammatory conditions linked to iron dysregulation pose significant challenges in neurodegenerative diseases. Iron-loaded microglia are observed in the brains of patients with various neuroinflammatory conditions, yet how iron overload affects microglial function and contributes to various neuroinflammatory processes is poorly understood. This in vitro study elucidates the relationship between excess iron, cofilin activation, and microglial function, shedding light on potential therapeutic avenues. Iron overload was induced in Human Microglial Clone 3 cells using ferrous sulfate, and the expressions of ferritin heavy chain, ferritin light chain, divalent metal transporter 1, cofilin, p-cofilin, nuclear factor-κB (NF-κB), and various inflammatory cytokines were analyzed using real-time quantitative polymerase chain reaction, immunocytochemistry, Western blotting, and enzyme-linked immunosorbent assay. Results revealed a notable increase in cofilin, NF-κB, and inflammatory cytokine expression levels following excess iron exposure. Moreover, treatment with deferoxamine (DFX), a known iron chelator, and a novel cofilin inhibitor (CI) synthesized in our laboratory demonstrate a mitigating effect on iron-induced cofilin expression. Furthermore, both DFX and CI exhibit promising outcomes in mitigating the inflammatory consequences of excess iron, including the expression of pro-inflammatory cytokines and NF-κB activation. These findings suggest that both DFX and CI can potentially alleviate microglia-induced neuroinflammation by targeting both iron dysregulation and cofilin-mediated pathways. Overall, this study provides valuable insights into iron-induced cofilin activation and microglial activation, offering avenues for potential targeted therapies for neuroinflammatory conditions associated with iron and cofilin dysregulation in neurodegenerative diseases.

Keywords:  NF‐κB; cofilin activation; iron overload; microglial activation; neuroinflammation

DOI:  https://doi.org/10.1111/jnc.16260
bioRxiv. 2024 Nov 04. pii: 2024.11.04.621917. [Epub ahead of print]

Pharmacological depletion of microglia protects against alcohol-induced corticolimbic neurodegeneration during intoxication in male rats.

Erika R Carlson, Jennifer K Melbourne, Kimberly Nixon.

Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causative role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia >90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.

DOI: https://doi.org/10.1101/2024.11.04.621917
Int Immunopharmacol. 2024 Nov 19. pii: S1567-5769(24)02114-3. [Epub ahead of print]144 113592

High-density lipoprotein alleviates ocular inflammation by downregulating M1 microglia and pyroptosis through regulating lipid accumulation and Caveolin-1 expression.

Enguang Chen, Han Chen, Yuan Yang, Miaomiao Liu, Jianhui Wang, Xuerui Zhang, Haodong Xiao, Jing Li, Huazhang Feng, Yu Xu.

  Uveitis encompasses a group of intraocular inflammatory diseases that are often associated with low levels of high-density lipoprotein (HDL). The role of HDL in intraocular inflammatory diseases remains unclear. In our research, we established an endotoxin-induced uveitis (EIU) model to investigate the role of HDL. Our study indicated that HDL could suppress ocular inflammation and restore retinal function in EIU mice. Specifically, HDL intervention effectively inhibited microglial activation and promoted the transformation of microglia from the M1 phenotype to the M2 phenotype. Furthermore, HDL intervention reduced microglial pyroptosis. Additionally, HDL was found to inhibit lipid accumulation in LPS-induced microglia, which is associated with inflammation, M1 polarization, and pyroptosis, by enhancing the expression of Caveolin-1 (CAV-1). Finally, we demonstrated that the function of HDL may be partially dependent on CAV-1 expression. We conclude that HDL inhibits pathological ocular inflammation by regulating M1/M2 phenotype polarization and pyroptosis through the modulation of lipid accumulation and CAV-1 expression. This suggests that HDL may represent a novel therapeutic strategy for ocular inflammation.

Keywords:  High-density lipoprotein; Lipid accumulation; Microglia; Ocular inflammation; Polarization; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2024.113592
Front Cell Neurosci. 2024 ;18 1430448

Outward depolarization of the microglia mitochondrial membrane potential following lipopolysaccharide exposure: a novel screening tool for microglia metabolomics.

Kendra I McGlothen, Rochelle M Hines, Dustin J Hines.

  Microglia are non-electrogenic immune cells that respond rapidly to protect the central nervous system (CNS) from infections, injuries, or other forms of damage. Microglia mitochondria are essential for providing the requisite energy resources for immune regulation. While fluctuations in energy metabolism are regulated by mitochondria and are reflected in the mitochondrial membrane potential (ΔΨm), there remains a lack of innovation in microglia-centric tools that capitalize on this. In this study, live imaging of microglia in acute slices from EGFP reporter mice expressing EGFP under the control of the fractalkine receptor (CX3CR1) promoter is combined with loading a fluorescent reporter of ΔΨm. Depolarizations in the ΔΨm were recorded after administering the well-characterized immune stimulant lipopolysaccharide (LPS). Microglia ΔΨm increased in distinctive phases with a relatively steep slope following LPS exposure. Conversely, the ΔΨm of neurons showed minimal regulation, highlighting a distinct microglia ΔΨm response to immune stimuli. Analysis of the depolarization of the microglia ΔΨm in the soma, branches, and endfeet revealed progressive changes in each subcellular domain originating in the soma and progressing outward. The inverse agonist emapunil attenuated the depolarization of the ΔΨm across states in a domain-specific manner. These findings emphasize the contribution of mitochondrial membrane dynamics in regulating microglial responses to immune stimuli. Further, this work advances a novel drug screening strategy for the therapeutic regulation of metabolic activity in inflammatory conditions of the brain.

Keywords:  emapunil; lipopolysaccharide; microglia; mitochondrial membrane potential; tetramethylrhodamine ethyl ester

DOI:  https://doi.org/10.3389/fncel.2024.1430448
Adv Sci (Weinh). 2024 Nov 18. e2412184

Microglial Lyzl4 Facilitates β-Amyloid Clearance in Alzheimer's Disease.

Jie Pan, Jie Zhong, Ji Geng, Jane Oberhauser, Shihua Shi, Jun Wan.

  Alzheimer's Disease (AD) is a neurodegenerative condition characterized by the accumulation and deposition of amyloid-β (Aβ) aggregates in the brain. Despite a wealth of research on the toxicity of Aβ and its role in synaptic damage, the mechanisms facilitating Aβ clearance are not yet fully understood. However, microglia, the primary immune cells of the central nervous system, are known to maintain homeostasis through the phagocytic clearance of protein aggregates and cellular debris. In this study, RNA sequencing analysis and live cell functional screens are employed to uncover microglial genetic modifiers related to AD. Lyzl4 is identified, which encodes a c-type lysozyme-like enzyme primarily localized to microglial lysosomes, as a gene significantly upregulated in AD microglia with aging and propose that Lyzl4 upregulation acts as a positive regulator of Aβ clearance. Furthermore, it is found that Lyzl4 overexpression boosts Aβ clearance both in vitro and in vivo, underscoring its potential for mitigating Aβ burden. These novel insights position Lyzl4 as a promising therapeutic target for Alzheimer's disease, paving the way for further exploration into potential AD treatments.

Keywords:  Alzheimer's disease (AD); Lyzl4; RNA‐seq; microglia; phagocytosis

DOI:  https://doi.org/10.1002/advs.202412184
Aging Cell. 2024 Nov 21. e14398

Residual microglia following short-term PLX5622 treatment in 5xFAD mice exhibit diminished NLRP3 inflammasome and mTOR signaling, and enhanced autophagy.

Maheedhar Kodali, Leelavathi N Madhu, Yogish Somayaji, Sahithi Attaluri, Charles Huard, Prashanta Kumar Panda, Goutham Shankar, Shama Rao, Bing Shuai, Jenny J Gonzalez, Chris Oake, Catherine Hering, Roshni Sara Babu, Sanya Kotian, Ashok K Shetty.

  While moderately activated microglia in Alzheimer's disease (AD) are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition using PLX5622 in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, astrocyte hypertrophy, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.

Keywords:  Alzheimer's disease; activated microglia; amyloid‐beta plaques; autophagy; chronic neuroinflammation; hippocampal neurogenesis; inflammasomes; mTOR signaling

DOI:  https://doi.org/10.1111/acel.14398
Mol Neurodegener. 2024 Nov 20. 19(1): 86

Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension.

Shubham Maurya, Maggie Lin, Shruthi Karnam, Tanirika Singh, Matangi Kumar, Emily Ward, Jeremy Sivak, John G Flanagan, Karsten Gronert.

   BACKGROUND: The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap.
METHODS: Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student's t-test and one-way ANOVA.
RESULTS: Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment.
CONCLUSION: We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway.

Keywords:  Glaucoma; Lipoxins; Microglia reactivity; Neurodegeneration; Optic nerve; Retina

DOI:  https://doi.org/10.1186/s13024-024-00775-z
bioRxiv. 2024 Nov 07. pii: 2024.11.06.622325. [Epub ahead of print]

TIA1 Mediates Divergent Inflammatory Responses to Tauopathy in Microglia and Macrophages.

Chelsea J Webber, Sophie J F van de Spek, Anna Lourdes Cruz, Sambhavi Puri, Cheng Zhang, Jacqueline T M Aw, Georgia-Zeta Papadimitriou, Rebecca Roberts, Kiki Jiang, Thuc Nhan Tran, Lushuang Zhang, Alexandria Taylor, Zihan Wang, Jacob Porter, Ionnis Sotiropoulos, Andrew Emili, Joana Silva, Hu Li, Benjamin Wolozin.

The RNA binding protein TIA1 is known to regulate stress responses. Here we show that TIA1 plays a much broader role in inflammatory cells, being required for the microglial sensome. We crossed TIA1 cKO mice (using a CX3CR1 driven cre element) to PS19 MAPT P301S tauopathy mice. The peripheral macrophages of TIA1 cKO mice exhibited a hyper-inflammatory phenotype with increased cytokine signaling, as expected. Surprisingly, the brains of these mice showed striking reductions in inflammation, including decreases in microglial inflammatory cytokines (TNFα and IL-1β) and sensome markers (CLEC7A, TREM2, ITGAX); these reductions were accompanied by corresponding decreases in tau pathology. Analysis of the brain TIA1 protein interactome identified brain selective TIA1 protein mediated pathways, including strong interactions with the microglial protein C1q, which directs pruning of dystrophic neurons. These results uncover a previously unknown regulatory role for TIA1 in microglial activation in the context of neurodegenerative disease and highlights the divergent regulation of two mononuclear phagocytic lineages: microglia and macrophages.

DOI: https://doi.org/10.1101/2024.11.06.622325
Immun Ageing. 2024 Nov 22. 21(1): 82

Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation.

Keerthana Chithanathan, Monika Jürgenson, Katrina Ducena, Anu Remm, Kalev Kask, Ana Rebane, Li Tian, Alexander Zharkovsky.

   BACKGROUND: MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.
RESULTS: Wild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo's therapeutic efficacy on miR-146a.
CONCLUSION: Elocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.

Keywords:  Elocalcitol; High-fat diet; Hypothalamus; Microglia; Senescence; miR-146a

DOI:  https://doi.org/10.1186/s12979-024-00485-6
Redox Biol. 2024 Nov 14. pii: S2213-2317(24)00406-3. [Epub ahead of print]78 103428

Aβ1-42 promotes microglial activation and apoptosis in the progression of AD by binding to TLR4.

Rui-Xia Dou, Ya-Min Zhang, Xiao-Juan Hu, Fu-Lin Gao, Lu-Lu Zhang, Yun-Hua Liang, Yin-Ying Zhang, Yu-Ping Yao, Li Yin, Yi Zhang, Cheng Gu.

Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases and the most devastating form of senile dementia. It has a complex mechanism and no effective treatment. Exploring the pathogenesis of AD and providing ideas for treatment can effectively improve the prognosis of AD. Microglia were incubated with β-amyloid protein 1-42 (Aβ1-42) to construct an AD cell model. After microglia were activated, cell morphology changed, the expression level of inflammatory factors increased, cell apoptosis was promoted, and the expression of microtubule-associated protein (Tau protein) and related proteins increased. By up-regulating and down-regulating Toll-like receptor 4 (TLR4), the cells were divided into TLR4 knockdown negative control group(Lv-NC group), TLR4 knockdown group(Lv-TLR4 group), TLR4 overexpression negative control group(Sh-NC group), and TLR4 overexpression group(Sh-TLR4 group). The expression of inflammatory factors was detected again. It was found that compared with the Lv-NC group, the expression of various inflammatory factors in the Lv-TLR4 group decreased, cell apoptosis was inhibited, and the expression of Tau protein and related proteins decreased. Compared with the Sh-NC group, the expression of inflammatory factors in the Sh-TLR4 group increased, cell apoptosis was promoted, and the expression of Tau protein and related proteins increased. These results indicate that Aβ1-42 may promote microglial activation and apoptosis by binding to TLR4. Reducing the expression of TLR4 can reduce the occurrence of inflammatory response in AD cells and slow down cell apoptosis. Therefore, TLR4 is expected to become a new target for the prevention and treatment of AD.

DOI: https://doi.org/10.1016/j.redox.2024.103428