Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Language: Английский

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TREM2 affects DAM-like cell transformation in the acute phase of TBI in mice by regulating microglial glycolysis

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 13, 2025

Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence function in the acute phase TBI remain unclear. Although glycolysis important for microglial differentiation, its regulatory role DAM transformation during still In this study, we investigated functions DAM-like cells mice, as well relationship between glycolysis. controlled cortical impact model was used to induce adult male wild-type (WT) C57BL/6 mice TREM2 knockout mice. Various techniques were assess effects on cells, including RT‒qPCR, immunofluorescence assays, behavioural tests, extracellular acidification rate (ECAR) Western blot analysis, cell magnetic sorting culture, glucose lactate flow cytometry. observed depended expression. impaired neurological recovery possibly due part clearing debris secreting VEGFa BDNF. Moreover, exhibited significantly increased glycolytic activity. regulated AKT‒mTOR‒HIF-1α pathway TBI. The increase partially contributed Taken together, results our study demonstrated that present might influence modulating Our provide new possible intervening

Language: Английский

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Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(1), P. 884 - 884

Published: Jan. 3, 2023

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) protein Tau aggregates are disease hallmarks key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to pathophysiology, as well. Microglia CNS-resident immune cells belonging myeloid lineage innate arm immunity. Under physiological conditions, constant motion order carry on their housekeeping function, they maintain an anti-inflammatory, quiescent state, with low expression cytokines no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, pathogens), acquire function overexpress cytokine gene modules. This process generally regarded activation implies production pro-inflammatory counterbalanced by synthesis release anti-inflammatory molecules. mechanism avoids excessive inflammatory response inappropriate microglial activation, which causes tissue damage brain homeostasis impairment. Once pathogenic stimulus cleared, activated return naïve, state. repeated (as case Aβ deposition early stage AD), shift toward less protective, neurotoxic phenotype, known “primed” microglia. The main characteristic primed lower capability turn back makes these prone chronic favours inflammation brain. Primed have impaired defence capacity against injury detrimental effects microenvironment. Additionally, priming associated onset progression represent promising target for treatment strategies. Many factors (genetics, environmental factors, baseline status microglia, ageing) generate aberrantly phenotype undergoes easier earlier than normally do. Novel, targets therapeutic strategies sought field and, importantly, among those influencing cells. CX3CL1 pathway could be valuable approach AD, although preliminary findings from studies this controversial. current review aims summarize state art role dysfunction pathogenesis proposes biochemical pathways possible treatment.

Language: Английский

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Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Nov. 29, 2023

Abstract Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed microglia. Several of these been recognized for their central roles microglial functions. Increasing evidence suggests that SHIP1, protein encoded by AD-associated gene INPP5D , is an important regulator phagocytosis and immune response. A recent study from our group identified SHIP1 a negative NLRP3 inflammasome human iPSC-derived cells (iMGs). In addition, we found connection between activity activation brain. The multiprotein complex induces secretion pro-inflammatory cytokines part innate responses against pathogens endogenous damage signals. Previously published suggested activated contributes to AD-related pathology. Here, provide overview current understanding context inflammation. We then review known intracellular functions including its role phosphoinositide signaling, interactions phagocytic receptors such TREM2 intersection signaling. Through rigorous examination intricate connections signaling pathways across several experimental systems postmortem analyses, field will be better equipped tailor newly emerging therapeutic strategies targeting neurodegenerative diseases.

Language: Английский

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Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 120, P. 54 - 70

Published: May 19, 2024

Language: Английский

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Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders

Biomolecules, Journal Year: 2023, Volume and Issue: 13(6), P. 922 - 922

Published: May 31, 2023

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate activation status microglia and neuroinflammation levels which are involved in pathogenesis SUDs. Several neuroimmune signaling pathways, including TLR/NF-кB, reactive oxygen species, mitochondria dysfunction, well autophagy defection, etc., implicated promoting Recently, inflammasome-mediated has identified playing critical roles induced by drugs. Among family inflammasomes, NOD-, LRR-, pyrin-domain-containing protein 3 (NLRP3) serves primary research target due to its abundant expression microglia. NLRP3 capability integrating multiple external internal inputs coordinately determining intensity under various pathological conditions. Here, we summarize effects on others, if any. The this topic is still at an infant stage; however, readily available findings suggest that inflammasome could be a common downstream effector stimulated play abused-drug-mediated biological through enhancing glia–neuron communications. might serve novel for ameliorating development

Language: Английский

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Neuroinflammation of microglia polarization in intracerebral hemorrhage and its potential targets for intervention

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Oct. 11, 2022

Microglia are the resident immune cells of central nervous system (CNS) and play a key role in neurological diseases, including intracerebral hemorrhage (ICH). activated to acquire either pro-inflammatory or anti-inflammatory phenotypes. After onset ICH, mediators produced by microglia at early stages serve as crucial character neuroinflammation. Conversely, switching microglial shift an phenotype could alleviate inflammatory response incite recovery. This review will elucidate dynamic profiles phenotypes their available following ICH. study can facilitate understanding self-regulatory functions involving Moreover, suggestions for future preclinical clinical research potential intervention strategies discussed.

Language: Английский

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Human microglial models to study host–virus interactions

Experimental Neurology, Journal Year: 2023, Volume and Issue: 363, P. 114375 - 114375

Published: March 11, 2023

Language: Английский

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Multi-target approach to Alzheimer’s disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms

Neurogenetics, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 1, 2025

Language: Английский

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Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(15)

Published: April 10, 2025

Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris cognition pruning synapses. Since liver X receptor β (LXRβ) has been identified as a regulator microglial homeostasis, this study examined whether its removal from microglia affects cognitive function. We used cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXRβ specifically. now report that ablation early postnatal life led reduction numbers, distinct morphological changes indicative activation, enhanced synapse engulfment accompanied deficits. Removal adult mice caused no defects. RNAseq analysis revealed loss reduced expression SAll1, master while increasing genes associated with activation CNS disease. This demonstrates distinctly different functions developing points long-term consequences defective signaling life.

Language: Английский

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