IL-4 and IL-10 promotes phagocytic activity of microglia by up-regulation of TREM2

Yi, Saini; Jiang, Xue; Tang, Xiaofang; Li, Yahui; Xiao, Chao; Zhang, Jinqiang; Zhou, Tao

doi:10.1007/s10616-020-00409-4

Cited by 21 publications

(12 citation statements)

References 42 publications

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“…A similar study shows that in human pluripotent stem cell (PSC), monocytes and transdifferentiated microglia-like cells, TREM2 R47H variant and loss of TREM2 on heterozygous or homozygous, display a significant decreased in phagocytosis [89]. On a recent finding, IL-4 and IL-10 enhance the phagocytosis of microglia via upregulation of TREM2 [90]. These findings support the hypothesis that reactive microglia and TREM2 are functionally necessary to alleviate neuronal damage.…”

Section: Trem2 Gets Involved In Ad Pathogenesis Via Microgliasupporting

confidence: 55%

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

Xu¹,

Ji²,

Sha³

et al. 2022

Hippocampus - Cytoarchitecture and Diseases

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Alzheimer’s disease (AD) is one of the most common causes of dementia all around the world. It is characterized by the deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFTs), which contribute to neuronal loss and cognitive decline. Microglia, as innate immune cells in brain, plays dual roles in the pathological process of AD. Expression in different subtypes of microglia is diverse in AD genes. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane glycoprotein mainly expressed on microglia in the central nervous system (CNS). Soluble TREM2 (sTREM2), a proteolytic product of TREM2, which is abundant in the cerebrospinal fluid, shows a dynamic change in different stages and ameliorates the pathological process of AD. The interplay between the different subtypes of apolipoprotein and TREM2 is closely related to the mechanism of AD and serves as important regulatory sites. Moreover, several therapeutic strategies targeting TREM2 have shown positive outcomes during clinical trials and some novel therapies at different points are in progress. In this review, we mainly talk about the interrelationships among microglia, TREM2, and AD, and hope to give an overview of the strategies of AD.

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Section: Trem2 Gets Involved In Ad Pathogenesis Via Microgliasupporting

confidence: 55%

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

Xu¹,

Ji²,

Sha³

et al. 2022

Hippocampus - Cytoarchitecture and Diseases

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“…The transition between M1/M2 microglia could potentially lead to novel treatment options and/or improve the actual TH. Depletion of anti-inflammatory cytokines has shown impaired oligodendrocytes maturation and subsequent hypomyelination of gray matter tracts as well as postnatal loss of cortical interneurons [ 101 ], while enhancing their secretion promotes the phagocytic activity and migration of microglia cells through apoptotic cells, explaining the relevant function of early expression in the clearing of dead cells after an insult [ 102 , 103 ].…”

Section: Discussionmentioning

confidence: 99%

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Bernis

Schleehuber

Zweyer

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hypoxic-ischemic encephalopathy (HIE) mainly affects preterm and term newborns, leading to a high risk of brain damage. Coexisting infection/inflammation and birth asphyxia are key factors associated with intracerebral increase of proinflammatory cytokines linked to HIE. Microglia are key mediators of inflammation during perinatal brain injury, characterized by their phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with pro- and anti-inflammatory cytokines as well as the nucleotide-binding domain, leucine-rich repeat protein (NLRP-3) inflammasome from microglia cells. For this purpose, we used our established neonatal rat model of inflammation-sensitized hypoxic-ischemic (HI) brain injury in seven-day-old rats. We assessed gene expression profiles of 11 cytokines and for NLRP-3 using real-time PCR from sorted CD11b/c microglia of brain samples at different time points (3.5 h after LPS injection and 0, 5, 24, 48, and 72 hours post HI) following different treatments: vehicle, E. coli lipopolysaccharide (LPS), vehicle/HI, and LPS/HI. Our results showed that microglia are early key mediators of the inflammatory response and exacerbate the inflammatory response following HI, polarizing into a predominant proinflammatory M1 phenotype in the early hours post HI. The brains only exposed to HI showed a delay in the expression of proinflammatory cytokines. We also demonstrated that NLRP-3 plays a role in the inflammatory resolution with a high expression after HI insult. The combination of both, a preinfection/inflammation condition and hypoxia-ischemia, resulted in a higher proinflammatory cytokine storm, highlighting the significant contribution of acute inflammation sensitizing prior to a hypoxic insult on the severity of perinatal brain damage.

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“…In our experiments, IL-4 persistently upregulated Arg-1 during 48 h, which correlated with the extension of several long lamellipodia, which contribute to immunoregulation. It also correlated with an increase in phagocytosis, which plays an important role in maintenance of brain homeostasis ( Fu et al, 2014 ; Yi et al, 2020 ). Disorders of microglial phagocytosis are implicated in many neurological diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury ischemic and other brain diseases ( Fu et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…CNS inflammation can be completely or partially prevented by resting microglia performing anti-inflammatory therapy in advance of inflammatory stimulation, which helps prevent damage caused by CNS inflammation ( Han et al, 2015 ; Zhang et al, 2017 ). What is more interesting is that microglia were stimulated with both pro-inflammatory and anti-inflammatory molecules, inducing hybrid phenotype with a variety of phenotypic characteristics ( Gomez-Nicola and Perry, 2015 ; Yi et al, 2020 ). Consistent with this, we showed here that microglia induced to adopt each of the three phenotypes could be switched to adopt either of the other two phenotypes, simply by changing the stimulating cytokine.…”

Section: Discussionmentioning

confidence: 99%

Mapping the Plasticity of Morphology, Molecular Properties and Function in Mouse Primary Microglia

Jiang

et al. 2022

Front. Cell. Neurosci.

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Microglia exert diverse functions by responding in diverse ways to different stimuli, yet little is known about the plasticity of various phenotypes that microglia display. We used interferon (IFN)-γ, interleukin (IL)-4 and IL-10 to induce different phenotypes in mouse primary microglia. RNA sequencing was used to identify genes differentially expressed in response to stimulation, and the different stimulated populations were compared in terms of morphology, proliferative capacity, phagocytic ability and neurotoxicity. IFN-γ induced an “immunodefensive” phenotype characterizing both induction of filopodia and upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor α. Microglia with this phenotype mediated an acute inflammatory response accompanied by excellent proliferative capacity and neurotoxicity, and remained susceptible to remodeling for up to 48 h after initial stimulation. IL-4 induced an enduring “neuroimmunoregulatory” phenotype involving induction of lamellipodium and persistent upregulation of arginase (Arg)-1 and YM-1 expression. Microglia with this phenotype remained susceptible to remodeling for up to 24 h after initial stimulation. IL-10 induced an “immunosuppressive” phenotype involving induction of ameba-like morphology and upregulation of transforming growth factor β and IL-10 as well as inhibition of inflammation. This phenotype was accompanied by inhibition of self-proliferation, while its morphology, molecular properties and function were the least susceptible to remodeling. IFN-γ, IL-4, or IL-10 appear to induce substantially different phenotypes in microglia. The immunodefensive microglia induced by IFN-γ showed remarkable plasticity, which may help repair CNS inflammation damage under pathological condition. Chronic activation with IL-10 decreases microglial plasticity, which may help protect the brain form the immune response. Our research justifies and guides further studies into the molecular pathways that operate in each phenotype to help multitasking microglia regulate homeostasis in the brain.

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IL-4 and IL-10 promotes phagocytic activity of microglia by up-regulation of TREM2

Cited by 21 publications

References 42 publications

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Mapping the Plasticity of Morphology, Molecular Properties and Function in Mouse Primary Microglia

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