Efferocytosis in the Central Nervous System

Zhao, Jiayi; Zhang, Weiqi; Wu, Tingting; Wang, Hongyi; Mao, Jialiang; Liu, Jian; Zhou, Ziheng; Lin, Xianfeng; Yan, Huige; Wang, Qingqing

doi:10.3389/fcell.2021.773344

Cited by 23 publications

(16 citation statements)

References 127 publications

(125 reference statements)

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“…38,39 Microglial efferocytosis, the efficient clearance of dead or dying cells, plays a crucial role in CNS diseases. 40,41 To investigate microglial efferocytosis after TBI and characterized the temporal profile of HDAC2-deficient microglia, we focused on the perilesional cortex and performed immunofluorescence staining for Iba1 and NeuN to label microglia and neurons, respectively (Figure 3(e) and (f)). In the non-injured sham brain hemisphere, resting microglia showed a ramified morphology, and the co-localization of Iba1 and NeuN was predominantly observed in the microglial processes (Figure 3(f), upper two panels).…”

Section: Resultsmentioning

confidence: 99%

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Zhang,

Zhao,

Wang

et al. 2023

J Cereb Blood Flow Metab

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The Class-I histone deacetylases (HDACs) mediate microglial inflammation and neurological dysfunction after traumatic brain injury (TBI). However, whether the individual Class-I HDACs play an indispensable role in TBI pathogenesis remains elusive. HDAC2 has been shown to upregulate pro-inflammatory genes in myeloid cells under brain injuries such as intracerebral hemorrhage, thereby worsening outcomes. Thus, we hypothesized that HDAC2 drives microglia toward a pro-inflammatory neurotoxic phenotype in a murine model of controlled cortical impact (CCI). Our results revealed that HDAC2 expression was highly induced in CD16/CD32+ pro-inflammatory microglia 3 and 7d after TBI. Surprisingly, microglia-targeted HDAC2 knockout (HDAC2 miKO) mice failed to demonstrate a beneficial phenotype after CCI/TBI compared to their wild-type (WT) littermates. HDAC2 miKO mice exhibited comparable levels of grey and white matter injury, efferocytosis, and sensorimotor and cognitive deficits after CCI/TBI as WT mice. RNA sequencing of isolated microglia 3d after CCI/TBI indicated the elevation of a panel of pro-inflammatory cytokines/chemokines in HDAC2 miKO mice over WT mice, and flow cytometry showed further elevated brain infiltration of neutrophils and B cells in HDAC2 miKO mice. Together, this study does not support a detrimental role for HDAC2 in microglial responses after TBI and calls for investigation into alternative mechanisms.

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Section: Resultsmentioning

confidence: 99%

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Zhang,

Zhao,

Wang

et al. 2023

J Cereb Blood Flow Metab

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“…through activation of the Gas6 signaling across several cell types. Although further investigation of the key axes in such complex crosstalk is needed, we speculate that Gas6 expressed by apoptotic cells activated efferocytosis, a well-known function of Mg in the brain, which allows the clearance of damaged apoptotic cells and prevents inflammation 56 . Further studies with a larger cohort of treated PDOXs will be needed to fully understand the adaptation of GBM cells with different molecular backgrounds and their adjacent TME.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

Yabo

Moreno-Sanchez

Pires‐Afonso

et al. 2023

Preprint

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BackgroundGlioblastoma (GBM) evades the immune system by creating an immune-suppressive tumor microenvironment (TME), where GBM-associated myeloid cells are geared towards tumor-supportive roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical. Here, we aim to understand the TME heterogeneity in GBM patients recapitulated in patient-derived orthotopic xenografts (PDOXs) and systematically characterize myeloid cell type identities at the molecular and functional level.MethodsWe applied single-cell RNA-sequencing and spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional assays to examine the heterogeneity of the TME in GBM. Various GBM PDOXs representing different tumor phenotypes were analyzed and compared to the patient tumors, normal brain and mouse GL261 glioma model.ResultsPDOX models recapitulate the major components of the TME detected in human GBM, where tumor cells reciprocally interact with host cells to create a GBM-specific TME. We detect the most prominent transcriptomic adaptations in myeloid cells, which are largely of microglial origin. We reveal intra-tumoral heterogeneity of microglia and identify diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia acquire dendritic cell-like features, displaying increased migration and phagocytosis. We further find novel microglial states expressing astrocytic and endothelial markers. Lastly, we show that temozolomide (TMZ) treatment leads to transcriptomic plasticity of both GBM tumor cells and adjacent TME components.ConclusionsOur data provide insight into the phenotypic adaptation of the heterogeneous TME instructed by GBM. We uncover that GBM-educated microglia are represented by various concomitant states, both in patients and recapitulated in PDOXs, displaying different pro- or anti-tumoral properties that are modulated by anti-neoplastic treatments, such as TMZ.KEY POINTSGBM-educated tumor microenvironment is faithfully recapitulated and modulated in PDOX modelsMicroglia represent an essential myeloid cell population in the GBM microenvironmentGBM-educated microglia acquire heterogeneous transcriptomic states across distinct tumor nichesGBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs, which are modulated upon TMZ treatmentIMPORTANCE OF THE STUDYThis manuscript addresses tumor-immune interactions in GBM, focusing on the molecular changes of the myeloid compartment. We find that myeloid cells, the most abundant immune cell population in brain tumors, undergo the most prominent transcriptional adaptation in the TME. Resident microglia represent the main myeloid cell population in the cellular tumor, while peripheral-derived myeloid cells appear to infiltrate the brain at sites of blood-brain barrier disruption. We identify reactive dendritic cell-like gene expression programs associated with enhanced phagocytic and antigen-presentation features in GBM-educated microglia subsets that might be harnessed for novel immunotherapeutic approaches. Overall, PDOX models faithfully recapitulate the major components of the GBM-educated TME and allow assessment of phenotypic changes in the GBM ecosystem upon treatment.

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“…Most tissues go through this process during their lifetime. 20 Efferocytosis, the process of eliminating ACs from the body, is crucial for both preserving the homeostasis of tissue in a disease-free state and reestablishing it following injury. 19 Using planned cell elimination, efferocytosis efficiently and quickly removes ACs from the body.…”

Section: Definition and Functions Of Efferocytosismentioning

confidence: 99%

“…Homeostasis is created and maintained in part through apoptosis. Most tissues go through this process during their lifetime 20 . Efferocytosis, the process of eliminating ACs from the body, is crucial for both preserving the homeostasis of tissue in a disease‐free state and reestablishing it following injury 19 .…”

Section: Definition and Functions Of Efferocytosismentioning

confidence: 99%

The role of fat‐soluble vitamins in efferocytosis

Jamalvandi,

Khayyatzadeh,

Hayati

et al. 2024

Cell Biochemistry & Function

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Cell death and the efficient removal of dead cells are two basic mechanisms that maintain homeostasis in multicellular organisms. efferocytosis, which includes four steps recruitment, recognition, binding and signaling, and engulfment. Effectively and quickly removes apoptotic cells from the body. Any alteration in efferocytosis can lead to several diseases, including autoimmune and inflammatory conditions, atherosclerosis, and cancer. A wide range of dietary components affects apoptosis and, subsequently, efferocytosis. Some vitamins, including fat‐soluble vitamins, affect different stages of efferocytosis. Among other things, by affecting macrophages, they are effective in the apoptotic cleansing of cells. Also, polyphenols indirectly intervene in efferocytosis through their effect on apoptosis. Considering that there are limited articles on the effect of nutrition on efferocytosis, in this article we will examine the effect of some dietary components on efferocytosis.

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Efferocytosis in the Central Nervous System

Cited by 23 publications

References 127 publications

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

The role of fat‐soluble vitamins in efferocytosis

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