bims-microg 2024-08-04 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024‒08‒04
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.
Residual Microglia Following Short-term PLX5622 Treatment in 5xFAD Mice Exhibit Diminished NLRP3 Inflammasome and mTOR Signaling, and Enhanced Autophagy.
Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.
Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.
Microglia Involvement into Acute and Chronic Brain Damage in Diabetic Rats: Impact of GLP-1RA and SGLT-2i.
Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury.
Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43Q331K ALS model mice.
Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.
T cell interactions with microglia in immune-inflammatory processes of ischemic stroke.
Autophagy-mediated activation of the AIM2 inflammasome enhances M1 polarization of microglia and exacerbates retinal neovascularization.
Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.
Elucidating Microglial Heterogeneity and Functions in Alzheimer's Disease Using Single-cell Analysis and Convolutional Neural Network Disease Model Construction.
Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain.
Physical Exercise Improves the Neuronal Function in Ischemic Stroke Via Microglial CB2R/P2Y12 Signaling.
Heterogeneity of cerebral atrophic rate in mild cognitive impairment and its interactive association with proteins related to microglia activity on longitudinal cognitive changes.
Interleukin-6 and interferon-alpha differentially regulate microglia function.
Microglial complex I activity: a crucial factor for smoldering inflammation in the central nervous system.
Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits.

Alzheimers Dement. 2024 Aug 01.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

Stephen P Schauer, Chang Hoon Cho, Gloriia Novikova, Gillie A Roth, Julie Lee, Anup D Sharma, Alejandro R Foley, Carl Ng, Philip Shen, Meena Choi, Taylur P Ma, Lilian Phu, Hanna G Budayeva, Tommy K Cheung, Guita Lalehzadeh, Jose Imperio, Hai Ngu, Ainhoa Etxeberria, Yuxin Liang, Mitchell G Rezzonico, Michelle Dourado, Kevin Huang, Zijuan Lai, Martha Hokom, Nikhil J Pandya, Dwight Newton, Alyaa M Abdel-Haleem, Pamela Chan, Donna Lee, Nardos G Tassew, Dewakar Sangaraju, Deborah O'Connor, Isidro Hötzel, Kimberly L Stark, Carolina Chou, Oded Foreman, Amy Easton, Kristin R Wildsmith, Gizette Sperinde, Christopher M Rose, Brad A Friedman, Reina N Fuji, Robby M Weimer, William J Meilandt, Shraddha Sadekar, Alicia A Nugent, Anne Biever.

  INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.METHODS: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering.
RESULTS: We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering.
DISCUSSION: CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain.
HIGHLIGHTS: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09. CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism. Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.

Keywords:  Alzheimer's disease; cerebrospinal fluid; chitinase‐3‐like protein 1; microglia; pharmacodynamic biomarker; triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1002/alz.13921
bioRxiv. 2024 Jul 16. pii: 2024.07.11.603157. [Epub ahead of print]

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.

Chronic neuroinflammation represents a prominent hallmark of Alzheimer's disease (AD). While moderately activated microglia are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations have indicated that the elimination of ∼80% of microglia through a month-long 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 without impacting Aβ levels. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the immediate effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglial phenotype or metabolic fitness are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition 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 demonstrated a noninflammatory phenotype, with highly branched and ramified processes and reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced in number with diminished Clec7a (dectin-1) expression. Additionally, both microglia and neurons displayed reduced mechanistic target of rapamycin (mTOR) signaling and autophagy. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling, and enhanced autophagy. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, 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.

DOI: https://doi.org/10.1101/2024.07.11.603157
J Neuroinflammation. 2024 Aug 02. 21(1): 192

Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

Xiaoyu Meng, Danpei Li, Ranran Kan, Yuxi Xiang, Limeng Pan, Yaming Guo, Peng Yu, Peiqiong Luo, Huajie Zou, Li Huang, Yurong Zhu, Beibei Mao, Yi He, Lei Xie, Jialu Xu, Xiaoyan Liu, Wenjun Li, Yong Chen, Suiqiang Zhu, Yan Yang, Xuefeng Yu.

  BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system.METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed.
RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage.
CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

Keywords:  Angiopoietin-like protein 8; Diabetes-associated cognitive dysfunction; Microglia; Neurons; Paired immunoglobulin-like receptor B

DOI:  https://doi.org/10.1186/s12974-024-03183-8
J Neuroinflammation. 2024 Jul 27. 21(1): 182

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Devin Wahl, Sydney J Risen, Shelby C Osburn, Tobias Emge, Sadhana Sharma, Vincenzo S Gilberto, Anushree Chatterjee, Prashant Nagpal, Julie A Moreno, Thomas J LaRocca.

  Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.

Keywords:  Aging; Cognitive function; NF-κB; NLRP3; Neuroinflammation; Tauopathy

DOI:  https://doi.org/10.1186/s12974-024-03182-9
Front Biosci (Landmark Ed). 2024 Jul 24. 29(7): 265

Microglia Involvement into Acute and Chronic Brain Damage in Diabetic Rats: Impact of GLP-1RA and SGLT-2i.

Anna Simanenkova, Oksana Fuks, Natalya Timkina, Alina Islamova, Dina Sufieva, Оlga Kirik, Dmitrii Korzhevskii, Timur Vlasov, Tatiana Karonova.

  BACKGROUND: Acute and chronic brain damage in type 2 diabetes mellitus (DM) determines the need to investigate the neuroprotective potential of glucose-lowering drugs. The purpose was to directly compare the neuroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with different duration of action and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in type 2 diabetic rats with and without stroke.METHODS: DM was modelled using high-fat diet and nicotinamide+streptozotocin protocol. The following groups (n = 15 each) were formed: DM without treatment, treatment with liraglutide, dulaglutide, canagliflozin as well as control group without DM and treatment. After 8 weeks, 10 rats from each group underwent middle cerebral artery occlusion. In the reperfusion period neurological deficit, neuroglial damage markers and brain necrosis were evaluated. Brain slices from the remaining 5 animals in each group were histologically examined for microglial activation and neuronal damage.
RESULTS: Brain damage was similar in "DM" and "Control" (17.53 [14.23; 26.58] and 15.87 [13.40; 22.68] % of total brain volume, respectively). All study drugs diminished damage volume comparing with "DM" and "Control" whereas the necrosis volume in "DM+Liraglutide" was smaller than in "DM+Canagliflozin" and did not significantly differ from "DM+Dulaglutide" (2.9 [1.83; 4.71], 6.17 [3.88; 8.88] and 4.57 [3.27; 7.90] %). The neurological deficit was more prominent in "DM" than in "Control", while all the drugs demonstrated similar positive effect. Neurofilament light chains (NLC) did not differ between "DM" and "Control". Dulaglutide and canagliflozin caused a marked decrease in NLC. Protein S100BB level was similar in "DM" and "Control". Liraglutide caused the largest S100BB decrease, while canagliflozin did not influence it. In chronic brain ischaemia, all drugs increased the number of normal neurons, but GLP-1RAs had a more pronounced effect. DM was accompanied by increased number of activated microglial cells in Cornu Ammonis (CA)1 hippocampal region. Both GLP-1RAs reduced the number of Iba-1-positive cells, with dulaglutide being more effective than liraglutide, whereas canagliflozin did not affect this parameter.
CONCLUSIONS: GLP-1RAs and SGLT-2i have neuroprotective properties against acute and chronic brain damage in diabetic rats, although the infarct-limiting effect of GLP-1RAs may be more pronounced. GLP-1RAs and SGLT-2i exert their protective effects by directly influencing neuronal survival, whereas GLP-1RAs also affect microglia.

Keywords:  GLP-1RAs; SGLT-2i; chronic brain damage; diabetes mellitus; microglia; neuroprotection; stroke

DOI:  https://doi.org/10.31083/j.fbl2907265
J Neuroinflammation. 2024 Aug 03. 21(1): 193

Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury.

Xuyang Hu, Jinxin Huang, Ziyu Li, Jianjian Li, Fangru Ouyang, Zeqiang Chen, Yiteng Li, Yuanzhe Zhao, Jingwen Wang, Shuisheng Yu, Juehua Jing, Li Cheng.

  Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy.

Keywords:  H4K12la; Lactate; Microglia; PD-1; Spinal cord injury

DOI:  https://doi.org/10.1186/s12974-024-03186-5
Neurobiol Dis. 2024 Jul 25. pii: S0969-9961(24)00214-6. [Epub ahead of print]200 106614

Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43Q331K ALS model mice.

Sang Won Cheung, Emily F Willis, David G Simmons, Mark C Bellingham, Peter G Noakes.

  Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43Q331K transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43Q331K mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43Q331K mice. In addition, TDP-43Q331K mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43Q331K mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43Q331K mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43Q331K mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43Q331K ALS mouse model.

Keywords:  Aggrecan; Amyotrophic lateral sclerosis (ALS); Astrocytes; Matrix metallopeptidase-9 (MMP-9); Microglia; Motor neuron; Motor neuron death; Motor neuron disease (MND); Oxidative stress; Perineuronal net (PNN); TDP-43(Q331K)

DOI:  https://doi.org/10.1016/j.nbd.2024.106614
Nat Commun. 2024 Jul 27. 15(1): 6340

Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.

Qilin Guo, Davide Gobbo, Na Zhao, Hong Zhang, Nana-Oye Awuku, Qing Liu, Li-Pao Fang, Tanja M Gampfer, Markus R Meyer, Renping Zhao, Xianshu Bai, Shan Bian, Anja Scheller, Frank Kirchhoff, Wenhui Huang.

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-50466-y
Neural Regen Res. 2025 May 01. 20(5): 1277-1292

T cell interactions with microglia in immune-inflammatory processes of ischemic stroke.

Yuxiao Zheng, Zilin Ren, Ying Liu, Juntang Yan, Congai Chen, Yanhui He, Yuyu Shi, Fafeng Cheng, Qingguo Wang, Changxiang Li, Xueqian Wang.

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke, which promotes neuronal death and inhibits nerve tissue regeneration. As the first immune cells to be activated after an ischemic stroke, microglia play an important immunomodulatory role in the progression of the condition. After an ischemic stroke, peripheral blood immune cells (mainly T cells) are recruited to the central nervous system by chemokines secreted by immune cells in the brain, where they interact with central nervous system cells (mainly microglia) to trigger a secondary neuroimmune response. This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke. We found that, during ischemic stroke, T cells and microglia demonstrate a more pronounced synergistic effect. Th1, Th17, and M1 microglia can co-secrete pro-inflammatory factors, such as interferon-γ, tumor necrosis factor-α, and interleukin-1β, to promote neuroinflammation and exacerbate brain injury. Th2, Treg, and M2 microglia jointly secrete anti-inflammatory factors, such as interleukin-4, interleukin-10, and transforming growth factor-β, to inhibit the progression of neuroinflammation, as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury. Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation, which in turn determines the prognosis of ischemic stroke patients. Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke. However, such studies have been relatively infrequent, and clinical experience is still insufficient. In summary, in ischemic stroke, T cell subsets and activated microglia act synergistically to regulate inflammatory progression, mainly by secreting inflammatory factors. In the future, a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells, along with the activation of M2-type microglia. These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01385
MedComm (2020). 2024 Aug;5(8): e668

Autophagy-mediated activation of the AIM2 inflammasome enhances M1 polarization of microglia and exacerbates retinal neovascularization.

Xianyang Liu, Qian Zhou, Jiayu Meng, Hangjia Zuo, Ruonan Li, Rui Zhang, Huiping Lu, Zhi Zhang, Hongshun Li, Shuhao Zeng, Meng Tian, Hong Wang, Ke Hu, Na Li, Liming Mao, Shengping Hou.

  Retinopathy of prematurity (ROP) is a retinal neovascularization (RNV) disease that is characterized by abnormal blood vessel development in the retina. Importantly, the etiology of ROP remains understudied. We re-analyzed previously published single-cell data and discovered a strong correlation between microglia and RNV diseases, particularly ROP. Subsequently, we found that reactive oxygen species reduced autophagy-dependent protein degradation of absent in melanoma 2 (AIM2) in hypoxic BV2 cells, leading to increased AIM2 protein accumulation. Furthermore, we engineered AIM2 knockout mice and observed that the RNV was significantly reduced compared to wild-type mice. In vitro vascular function assays also demonstrated diminished angiogenic capabilities following AIM2 knockdown in hypoxic BV2 cells. Mechanistically, AIM2 enhanced the M1-type polarization of microglia via the ASC/CASP1/IL-1β pathway, resulting in RNV. Notably, the administration of recombinant protein IL-1β exacerbated angiogenesis, while its inhibition ameliorated the condition. Taken together, our study provides a novel therapeutic target for ROP and offers insight into the interaction between pyroptosis and autophagy.

Keywords:  AIM2 inflammasomes; autophagy; microglia; retinal angiogenesis; retinopathy of prematurity

DOI:  https://doi.org/10.1002/mco2.668
bioRxiv. 2024 Jul 28. pii: 2024.07.28.605493. [Epub ahead of print]

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

Di Zhang, Leslie A Rubio Rodríguez-Kirby, Yingxin Lin, Mengyi Song, Li Wang, Lijun Wang, Shigeaki Kanatani, Tony Jimenez-Beristain, Yonglong Dang, Mei Zhong, Petra Kukanja, Shaohui Wang, Xinyi Lisa Chen, Fu Gao, Dejiang Wang, Hang Xu, Xing Lou, Yang Liu, Jinmiao Chen, Nenad Sestan, Per Uhlén, Arnold Kriegstein, Hongyu Zhao, Gonçalo Castelo-Branco, Rong Fan.

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag- RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

DOI: https://doi.org/10.1101/2024.07.28.605493
Sci Rep. 2024 Jul 27. 14(1): 17271

Elucidating Microglial Heterogeneity and Functions in Alzheimer's Disease Using Single-cell Analysis and Convolutional Neural Network Disease Model Construction.

Xinyi Wu, Mingyu Liu, Xinyue Zhang, Xue Pan, Xiaotong Cui, Jiahui Jin, Huanan Sun, Chuyu Xiao, Xiangyi Tong, Liou Ren, Yaxuan Wang, Xuezhao Cao.

  In this study, we conducted an in-depth exploration of Alzheimer's Disease (AD) by integrating state-of-the-art methodologies, including single-cell RNA sequencing (scRNA-seq), weighted gene co-expression network analysis (WGCNA), and a convolutional neural network (CNN) model. Focusing on the pivotal role of microglia in AD pathology, our analysis revealed 11 distinct microglial subclusters, with 4 exhibiting obviously alterations in AD and HC groups. The investigation of cell-cell communication networks unveiled intricate interactions between AD-related microglia and various cell types within the central nervous system (CNS). Integration of WGCNA and scRNA-seq facilitated the identification of critical genes associated with AD-related microglia, providing insights into their involvement in processes such as peptide chain elongation, synapse-related functions, and cell adhesion. The identification of 9 hub genes, including USP3, through the least absolute shrinkage and selection operator (LASSO) and COX regression analyses, presents potential therapeutic targets. Furthermore, the development of a CNN-based model showcases the application of deep learning in enhancing diagnostic accuracy for AD. Overall, our findings significantly contribute to unraveling the molecular intricacies of microglial responses in AD, offering promising avenues for targeted therapeutic interventions and improved diagnostic precision.

Keywords:  Alzheimer’s disease; Convolutional neural network; Microglia; scRNA-seq

DOI:  https://doi.org/10.1038/s41598-024-67537-1
Pain. 2024 Jul 30.

Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain.

Elizabeth I Sypek, Adrien Tassou, Hannah Y Collins, Karen Huang, William M McCallum, Alexandra T Bourdillon, Ben A Barres, Christopher J Bohlen, Grégory Scherrer.

ABSTRACT: Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies.

DOI: https://doi.org/10.1097/j.pain.0000000000003275
Mol Neurobiol. 2024 Jul 27.

Physical Exercise Improves the Neuronal Function in Ischemic Stroke Via Microglial CB2R/P2Y12 Signaling.

Xiao-Fei He, Xiao-Feng Yang, Ge Li, Yun Zhao, Jing Luo, Jing-Hui Xu, Hai-Qing Zheng, Li-Ying Zhang, Xi-Quan Hu.

  Physical exercise (PE) may be the single most important and accessible lifestyle habit throughout life, it inhibits the neuroinflammatory response and protects the brain against damage. As the innate cells in brain, microglia undergo morphological and functional changes to communicate with neurons protecting the neurons from injury. Herein, aiming at exploring the effects of PE on the communication between microglia-neuron during acute ischemic cerebral infarction, we carried out running wheel training before the conduction of transient middle cerebral artery occlusion (tMCAO) in C57BL/6 J and Cx3cr1-GFP mice. We found that microglial P2Y12 expression in the peri-infarct area was decreased, microglial dynamics and microglia-neuron communications were impaired, using in vivo two-photon imaging. PE up-regulated the microglial P2Y12 expression, increased the microglial dynamics, and promoted the contacts of microglia with neurons. As a result, PE inhibited neuronal Ca2+ overloads and protected against damage of the neuronal mitochondria in acute tMCAO. Mechanistically, PE increased the cannabinoid receptor 2 (CB2R) in microglia, promoted the phosphorylation of Nrf2 (NF-E2-related factor 2) at ser-344, increased the transcription factor level of Mafk, and up-regulated the level of P2Y12, whereby PE increased the levels of CB2R to promote microglia-neuron contacts to monitor and protect neuronal function.

Keywords:  CB2R-P2Y12 Signaling; Exercise; Ischemic Stroke; Microglia—Neuron Contacts

DOI:  https://doi.org/10.1007/s12035-024-04391-2
Arch Gerontol Geriatr. 2024 Jul 19. pii: S0167-4943(24)00258-9. [Epub ahead of print]127 105582

Heterogeneity of cerebral atrophic rate in mild cognitive impairment and its interactive association with proteins related to microglia activity on longitudinal cognitive changes.

Alzheimer's Disease Neuroimaging Initiative

  BACKGROUND: Heterogeneity of cerebral atrophic rate commonly exists in mild cognitive impairment (MCI), which may be associated with microglia-involved neuropathology and have an influence on cognitive outcomes.OBJECTIVE: We aim to explore the heterogeneity of cerebral atrophic rate among MCI and its association with plasma proteins related to microglia activity, with further investigation of their interaction effects on long-term cognition.
SUBJECTS: A total of 630 MCI subjects in the ADNI database were included, of which 260 subjects were available with baseline data on plasma proteins.
METHODS: Group-based multi-trajectory modeling (GBMT) was used to identify the latent classes with heterogeneous cerebral atrophic rates. Associations between latent classes and plasma proteins related to microglia activity were investigated with generalized linear models. Linear mixed effect models (LME) were implemented to explore the interaction effects between proteins related to microglia activity and identified latent classes on longitudinal cognitive changes.
RESULTS: Two latent classes were identified and labeled as the slow-atrophy class and the fast-atrophy class. Associations were found between such heterogeneity of atrophic rates and plasma proteins related to microglia activity, especially AXL receptor tyrosine kinase (AXL), CD40 antigen (CD40), and tumor necrosis factor receptor-like 2 (TNF-R2). Interaction effects on longitudinal cognitive changes showed that higher CD40 was associated with faster cognitive decline in the slow-atrophy class and higher AXL or TNF-R2 was associated with slower cognitive decline in the fast-atrophy class.
CONCLUSIONS: Heterogeneity of atrophic rates at the MCI stage is associated with several plasma proteins related to microglia activity, which show either protective or adverse effects on long-term cognition depending on the variability of atrophic rates.

Keywords:  Alzheimer's disease; Cerebral atrophy; Group-based multi-trajectory modeling; Microglial proteins; Mild cognitive impairment

DOI:  https://doi.org/10.1016/j.archger.2024.105582
Neuropathol Appl Neurobiol. 2024 Aug;50(4): e13003

Interleukin-6 and interferon-alpha differentially regulate microglia function.

Rovin Verdillo, Alanna Spiteri, Barney Viengkhou, Claire Wishart, Nicholas J C King, Markus J Hofer.

  Previous reports have shown that IL-6 and IFN-⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL-6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN-⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine-mediated neuroinflammatory diseases.

Keywords:  interferon‐alpha; interleukin‐6; microglia; migration; phagocytosis

DOI:  https://doi.org/10.1111/nan.13003
Signal Transduct Target Ther. 2024 Jul 31. 9(1): 185

Microglial complex I activity: a crucial factor for smoldering inflammation in the central nervous system.

Jana K Sonner, Christina Mayer, Manuel A Friese.

DOI: https://doi.org/10.1038/s41392-024-01894-1
Mol Psychiatry. 2024 Aug 02.

Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits.

Ashutosh Tripathi, Alona Bartosh, Jocelyn Mata, Chale Jacks, Amit Kumar Madeshiya, Usama Hussein, L Elliot Hong, Zhongming Zhao, Anilkumar Pillai.

Inflammation and synapse loss have been associated with deficits in social behavior and are involved in pathophysiology of many neuropsychiatric disorders. Synapse loss, characterized by reduction in dendritic spines can significantly disrupt synaptic connectivity and neural circuitry underlying social behavior. Chronic stress is known to induce loss of spines and dendrites in the prefrontal cortex (PFC), a brain region implicated in social behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of type I Interferon (IFN-I) signaling in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found increased expression of type I IFN receptor (IFNAR) in microglia following CUS. Conditional knockout of microglial IFNAR in adult mice rescued CUS-induced social behavior deficits and synapse loss. Bulk RNA sequencing data show that microglial IFNAR deletion attenuated CUS-mediated changes in the expression of genes such as Keratin 20 (Krt20), Claudin-5 (Cldn5) and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. Cldn5 and Nr4a1 are known for their roles in synaptic plasticity. Krt20 is an intermediate filament protein responsible for the structural integrity of epithelial cells. The reduction in Krt20 following CUS presents a novel insight into the potential contribution of cytokeratin in stress-induced alterations in neuroplasticity. Overall, these results suggest that microglial IFNAR plays a critical role in regulating synaptic plasticity and social behavior deficits associated with chronic stress conditions.

DOI: https://doi.org/10.1038/s41380-024-02675-6