Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity

Shemer, Anat; Jung, Steffen

doi:10.1007/s00281-015-0519-z

Cited by 61 publications

(54 citation statements)

References 135 publications

(179 reference statements)

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“…Cd11b is an integral membrane-associated protein that is a cellular marker of CNS microglia; however, Cd11b is also present on the surface of other monocyte-derived lineages, including macrophages. Macrophages are capable of invading the CNS, sparking neuroinflammation and neurodegeneration (Shemer and Jung, 2015). MGM15, MGM3, and MGM13 were further assessed for unintended non-microglial cellular gene expression arising from Cd11b+ enrichment.…”

Section: 3 Results and Discussionmentioning

confidence: 99%

Microglial-specific transcriptome changes following chronic alcohol consumption

et al. 2018

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Microglia are fundamentally important immune cells within the central nervous system (CNS) that respond to environmental challenges to maintain normal physiological processes. Alterations in steady-state cellular function and over-activation of microglia can facilitate the initiation and progression of neuropathological conditions such as Alzheimer’s disease, Multiple Sclerosis, and Major Depressive Disorder. Alcohol consumption disrupts signaling pathways including both innate and adaptive immune responses that are necessary for CNS homeostasis. Coordinate expression of these genes is not ascertained from an admixture of CNS cell-types, underscoring the importance of examining isolated cellular populations to reveal systematic gene expression changes arising from mature microglia. Unbiased RNA-Seq profiling was used to identify gene expression changes in isolated prefrontal cortical microglia in response to recurring bouts of voluntary alcohol drinking behavior. The voluntary ethanol paradigm utilizes long-term consumption ethanol that results in escalated alcohol intake and altered cortical plasticity that is seen in humans. Gene coexpression analysis identified a coordinately regulated group of genes, unique to microglia, that collectively are associated with alcohol consumption. Genes within this group are involved in toll-like receptor signaling and transforming growth factor beta signaling. Network connectivity of this group identified Siglech as a putative hub gene and highlighted the potential importance of proteases in the microglial response to chronic ethanol. In conclusion, we identified a distinctive microglial gene expression signature for neuroimmune responses related to alcohol consumption that provides valuable insight into microglia-specific changes underlying the development of substance abuse, and possibly other CNS disorders.

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Section: 3 Results and Discussionmentioning

confidence: 99%

Microglial-specific transcriptome changes following chronic alcohol consumption

et al. 2018

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“…The importance of developing methods to distinguish microglia from hematopoietic myeloid cells becomes increasingly clear, with an ever-increasing number of studies revealing differential roles of these monocytic cells in various CNS diseases (33,34). Differential functions of microglial cells can be partially attributed to their unique origin from yolk sac progenitors (29) and the fact that they can maintain themselves by virtue of longevity and self-renewal (29,35,36).…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

et al. 2017

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In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we employed two genetically engineered mouse models where oncogenic drivers and fluorescent reporters were expressed coordinately under the control of the monocyte/microglia-selective Cx3cr1 or Ccr2 promoters, respectively. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the glioblastoma, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/monocytes constituted ~85% of the total TAM population, with resident microglia accounting for the ~15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via Ccl2 genetic ablation prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm.

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“…Recent studies from our lab have addressed this void by cell-specific gene targeting approaches, demonstrating that oligodendroglial TNFR2 promotes oligodendrocyte differentiation and remyelination in experimental autoimmune encephalomyelitis (EAE), a model of MS (Madsen PM, 2016). Microglia and monocytes/macrophages (Mo/MΦ) play critical roles in MS and EAE (Shemer and Jung, 2015), and both express TNFR2 (Brambilla et al, 2011). However, the current knowledge of TNFR2 function in these populations is limited to only two in vitro studies: in microglia, TNFR2 was shown to promote the expression of antiinflammatory and neuroprotective genes (Veroni et al, 2010), and in macrophages to play an auxiliary role in activating proinflammatory TNFR1 signaling (Ruspi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

et al. 2017

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Summary In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation, and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

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Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity

Cited by 61 publications

References 135 publications

Microglial-specific transcriptome changes following chronic alcohol consumption

Microglial-specific transcriptome changes following chronic alcohol consumption

Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

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