Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Abstract Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in defense, surveillance, and homeostasis. This review systematically discusses types of hematopoietic progenitors that give rise macrophages, including primitive progenitors, erythro-myeloid stem cells. These have distinct genetic backgrounds developmental processes. Accordingly, macrophages exhibit complex diverse functions body, phagocytosis clearance cellular debris, antigen presentation, response, regulation inflammation cytokine production, tissue remodeling repair, multi-level regulatory signaling pathways/crosstalk involved homeostasis physiology. Besides, tumor-associated a key component TME, exhibiting both anti-tumor pro-tumor properties. Furthermore, functional status is closely linked development various diseases, cancer, autoimmune disorders, cardiovascular disease, neurodegenerative metabolic conditions, trauma. Targeting has emerged as promising therapeutic strategy these contexts. Clinical trials macrophage-based targeted drugs, immunotherapies, nanoparticle-based therapy were comprehensively summarized. Potential challenges future directions targeting also been discussed. Overall, our highlights significance this versatile cell human health which expected inform research clinical practice.

Language: Английский

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Integrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

Abstract Astrocytes, a type of glial cell in the central nervous system (CNS), adopt diverse states response to injury that are influenced by their location relative insult. Here, we describe platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO ( tissue- digital microfluidic isolation single cells -Omics). We use alongside two high-throughput platforms spatial (Visium) (10X Chromium) examine heterogeneity astrocyte cortical ischemic stroke male mice. show integration Visium 10X Chromium datasets infers populations, proximal or distal site, while determines boundaries molecular profiles define these populations. find astrocytes differences lipid shuttling, with enriched expression Apoe Fabp5 . Our provide resource understanding roles showcase utility hypothesis-driven, resolved experiments.

Language: Английский

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Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 15, 2024

The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in maintenance and regulation network dynamics. Research on microglia, resident innate immune has advanced considerably recent years, our understanding their diverse functions continues to grow. Microglia play critical roles formation synapses, myelination, responses injury, neurogenesis, inflammation, many other physiological processes. In parallel with advances microglial biology, cutting-edge techniques characterization properties have emerged increasing depth precision. Labeling tools reporter models important study morphology, ultrastructure, dynamics, but also isolation, which required glean key phenotypic information through single-cell transcriptomics emerging approaches. Strategies selective depletion modulation can provide novel insights into microglia-targeted treatment strategies neuropsychiatric neurodegenerative conditions, cancer, autoimmunity. Finally, fate mapping as tool answer fundamental questions about including origin, migration, proliferation throughout lifetime organism. This review aims comprehensive discussion these established techniques, applications microglia development, homeostasis, CNS pathologies.

Language: Английский

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Infiltrating peripheral monocyte TREM-1 mediates dopaminergic neuron injury in substantia nigra of Parkinson’s disease model mice

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 14, 2025

Abstract Neuroinflammation is a key factor in the pathogenesis of Parkinson’s disease (PD). Activated microglia central nervous system (CNS) and infiltration peripheral immune cells contribute to dopaminergic neuron loss. However, role responses, particularly triggering receptor expressed on myeloid cells-1 (TREM-1), PD remains unclear. Using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced mouse model, we examined TREM-1 expression monocyte substantia nigra pars compacta (SNpc). We found that MPTP increased monocytes, deletion monocytes protected against neurotoxicity SNpc. inhibition, both genetically pharmacologically, reduced infiltration, alleviated neuroinflammation, preserved neurons, resulting improved motor function. Furthermore, adoptive transfer TREM-1-expressing from model mice naive induced neuronal damage deficits. These results underscore critical progression, suggesting targeting could be promising therapeutic approach prevent neurodegeneration dysfunction PD.

Language: Английский

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Microglia targeting by adeno-associated viral vectors

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 5, 2024

Microglia play a crucial role in maintaining homeostasis of the central nervous system and they are actively involved shaping brain’s inflammatory response to stress. Among multitude molecules, purinergic receptors enzymes special importance due their ability regulate microglia activation. By investigating mechanisms underlying microglial responses dysregulation, researchers can develop more precise interventions modulate behavior alleviate neuroinflammatory processes. Studying gene function selectively microglia, however, remains technically challenging. This review article provides an overview adeno-associated virus (AAV)-based targeting approaches, discussing potential prospects for refining these approaches improve both specificity effectiveness encouraging future investigations aimed at connecting AAV-mediated therapeutic benefit neurological disorders.

Language: Английский

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Crosstalk Among Gut Microbiota, Fecal Metabolites, and Amygdala Neuropathology Genes After Ginger Polyphenol Administration in Female Rats with Neuropathic Pain: Evidence for Microbiota–Gut–Brain Connection

Nutrients, Journal Year: 2025, Volume and Issue: 17(9), P. 1444 - 1444

Published: April 25, 2025

Objectives. The relationships among neuropathic pain, gut microbiota, microbiome-derived metabolites, and neuropathology have received increasing attention. This study examined the effects of two dosages gingerol-enriched ginger (GEG) on mechanical hypersensitivity, anxiety-like behavior, microbiome composition its markers in female rats spinal nerve ligation (SNL) model pain. Methods. Forty were assigned to 4 groups: sham-vehicle, SNL-vehicle, SNL+GEG at 200 mg/kg BW, 600 BW via oral gavage. All animals given an AIN-93G diet for 5 weeks. Mechanical hypersensitivity was assessed by von Frey test. Anxiety-like behavior open field Fecal microbiota metabolites determined using 16S rRNA gene sequencing GC-MS, respectively. Neuropathology expression profiling amygdala nCounter® pathway panel. Results. Both GEG-treated groups showed decreased SNL model. Gut diversity both GEG compared with untreated rats. In model, phyla such as Bacteroidota, Proteobacteria Verrucomicrobiota decreased. Compared group, exhibited increased abundance Bacteroidota (i.e., Rikenella, Alistipes, Muribaculaceae, Odoribacter), Firmicutes UBA1819, Ruminococcaceae, Oscillospiraceae, Roseburia), Victivallis). had higher levels nine hydrophilic positive [val-glu, urocanic acid, oxazolidinone, L-threonine, L-norleucine, indole, imino-tryptophan, 2,3-octadiene-5,7-diyn-1-ol, (2E)-3-(3-hydroxyphenyl) acrylaldehyde] negative [methylmalonic acid metaphosphoric acid], well lower five [xanthine, N-acetylmuramic doxaprost, adenine, 1-myristoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine]. Among 770 genes, 1 (PLA2G4A) upregulated 2 genes (CDK5R1 SHH) downregulated caused upregulation (APC, CCNH, EFNA5, GRN, HEXB, ITPR1, PCSK2, TAF9, WFS1) downregulation three (AVP, C4A, TSPO) amygdala. Conclusions. supplementation mitigated pain-associated behaviors part reversing molecular signature associated changes fecal which could play a role mediating

Language: Английский

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Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes

Immunity, Journal Year: 2024, Volume and Issue: 57(9), P. 2216 - 2231.e11

Published: Aug. 15, 2024

Language: Английский

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Alpha-Synuclein and Microglia in Parkinson’s Disease: From Pathogenesis to Therapeutic Prospects

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(23), P. 7243 - 7243

Published: Nov. 28, 2024

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor symptoms and non-motor features. A hallmark of PD the misfolding accumulation alpha-synuclein (α-syn), which triggers neuroinflammation drives neurodegeneration. Microglia, brain cells that play central role in neuroinflammatory responses help clear various unnecessary molecules within brain, thus maintaining brain's internal environment, respond to α-syn through mechanisms involving inflammation, propagation, clearance. This review delves into complex interplay between microglia, elucidating how these interactions drive pathogenesis. Furthermore, we discuss emerging therapeutic strategies targeting α-syn-microglia axis, with focus on modulating microglial functions mitigate neuroinflammation, enhance clearance, prevent emphasizing their potential slow progression.

Language: Английский

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Emerging Techniques for the Study of Microglia: Visualization, Depletion and Fate Mapping

Published: Aug. 31, 2023

The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in maintenance and regulation network dynamics. Research on microglia, resident innate immune has advanced considerably recent years, our understanding their diverse functions continues to grow. Microglia play critical roles formation synapses, myelination, responses injury, neurogenesis, inflammation many other physiological processes. In parallel with advances microglial biology, cutting-edge techniques characterization properties have emerged increasing depth precision. Labeling tools reporter models important study morphology, ultrastructure dynamics, but also isolation, which required glean key phenotypic information through single-cell transcriptomics emerging approaches. Strategies selective depletion modulation can provide novel insights into microglia-targeted treatment strategies neuropsychiatric neurodegenerative conditions, cancer autoimmunity. Finally, fate mapping as tool answer fundamental questions about including origin, migration proliferation throughout lifetime organism. This review aims comprehensive discussion these techniques, applications microglia development, homeostasis CNS pathologies.

Language: Английский

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Eradication of human immunodeficiency virus-1 reservoir in the brain microglia

Neural Regeneration Research, Journal Year: 2022, Volume and Issue: 18(3), P. 552 - 552

Published: Aug. 22, 2022

Human immunodeficiency virus-1 (HIV) reservoirs in the human brain: Antiretroviral therapy (ART) effectively decreases active HIV replication to undetectable levels. Therefore, it greatly improves quality of life for people living with (PLWH). However, except a few exceptional cases after stem-cell transplantation from CCR5Δ32 mutation donors, such as Berlin and London patients, there is no cure HIV, due latent harbored long-lived permissive cells. quickly rebounds upon disruption ART, causing life-long burden ART PLWH order control viral replication. Similar peripheral blood, establishes brain very early infection (Putatunda et al., 2019), which associated HIV-associated neurocognitive disorders despite PLWH, potentially caused directly by residual or indirectly neuroinflammation. Animal model studies suggest that myeloid cells (BMCs) are latently infected contribute central nervous system (CNS) (Honeycutt 2016; Avalos 2017). To achieve replication-competent hosted both periphery CNS must be targeted eradication strategies. It remains determined cell types serve stable brain. DNA RNA was detectable BMCs, astrocytes, pericytes, neural stem cells, oligodendrocytes, CD4+ T Bertrand 2019; Putatunda 2019). As one major immune self-renewable resident microglia act first line defense against (Ajami 2007). especially microglia, express CCR5 low levels CD4 (Gumbs 2022), can productive infection, allowing persistent serving bona fide CNS. Blood-borne monocyte-derived macrophages (MDMs) constitute 5–10% total BMCs (Ginhoux 2010). MDMs originate perivascular regions terminally differentiated frequently replenished hematopoietic progenitors. short lifespan (~ months) lack self-renewal potential, unclear whether support long-lasting brain, prerequisite feature any reservoir. While astrocytes were egress an astrocyte-implanted mouse (Lutgen 2020), reservoir Most recently, blood-brain barrier pericytes reported unique source possibly established latency (Bertrand defined potential another Together, curative strategies target would permit ART-free remission prevent neuronal dysfunction, neuroinflammation, disorder progression For example, has been shown activation damage linked development tools specifically step achieving Brain cure: “Shock kill” proposed HIV. originated idea that: 1) Latent does not efficiently components its particles via blocks transcription and/or translation, hiding compromised surveillance PLWH. 2) If disrupted itself reversal, i.e. proteins, RNA, particles, could eradicated following killing strategies, including enhanced responses, neutralizing antibodies, direct killing. may induce injury other side effects (Proust 2020). alternative being developed avoid this caveat without among gene editing knock out genome (Yin initially recent have CRISPR/Cas vivo although efficiency specificity Two aspects technologies improved therapeutic approach CNS: Efficient delivery gene-editing into Specific harboring proviruses. Fortunately, state-of-the-art applied discover genes exclusively expressed subset One HexB, uniquely but (Masuda even under pathological conditions This property makes HexB promoter excellent candidate microglia-specific targeting injury. We recently characterized small-sized version (134 bp) (Shah drives expression largely astrocytes. Interestingly, 135 bp CD68 also identified study, similarly induces over 2022). These promoters elements ideal packaging capacity transduction adeno-associated virus (AAV), best systems therapy. Future work will determine activity non-microglia vivo. mentioned above, essential tool deliver editor so proviruses way develop microglia-tropic AAV serotype cross facilitate cellular (Rosario 2016). Investigation underway currently available serotypes. Combination effective selectively further improve reduce during editing. Lastly, obstacle penetration needs overcome design Alvarez-Carbonell The remaining hurdle study appropriate test tool. HIV-infected humanized mice simian virus-infected rhesus macaques able resemble suppression establishment models expensive require high standards facilities house animals. There emerging cerebral organoid models, three-dimensional culture recapitulates suitable study. Nevertheless, most these where exogenous incorporated mini-brains maturation. native microglia-containing (MCO) allow co-receptor (Bodnar 2021; Gumbs established, proper strategy MCO. Currently, vitro microglia. Microglia isolated fresh Unfortunately, resources limited isolation, culture, maintenance tissues tremendous challenges ex studies. In collaboration “Last Gift” cohort, we establishing protocol isolate highly pure post-mortem brains receiving long-term ART. novel technology provide us physiologically relevant platform, enabling closely reservoirs. Summary future perspectives: at infant stage characterize (Figure 1). uncertain eradicated. Despite that, attack help better understand persistence, useful fight infections future.Figure 1: Road map editing.Post-mortem ART-suppressed SIV-infected NHPs (hu-mice) MCO primary MG necessary complement vitro. utilized Central system; HIV: virus-1; MCO: MG-containing organoid; MG: microglia; NHP: Non-human primate; PLWH: HIV; SIV: virus.We apologize cite all publications limitation citations. GJ supported Qura Therapeutics, R01DA055491, UM1 AI164567, P30AI50410 R21MH128034. Availability data materials:All generated analyzed included published article supplementary information files. Open peer reviewer:Mengmeng Jin, Rutgers University - Busch Campus, USA Additional file:Open review report 1.P-Reviewer: Jin M; C-Editors: Zhao M, Liu WJ, Wang Lu; T-Editor: Jia Y

Language: Английский

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