Microglia and central nervous system immunity.

Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, One Shrader Street, Suite 650, San Francisco, CA 94117, USA.
Neurosurgery clinics of North America (Impact Factor: 1.54). 01/2010; 21(1):43-51. DOI: 10.1016/
Source: PubMed

ABSTRACT The central nervous system (CNS) has evolved as an immune-privileged site to protect its vital functions from damaging immune-mediated inflammation. There must be a CNS-adapted system of surveillance that continuously evaluates local changes in the nervous system and communicates to the peripheral immune system during an injury or a disease. Recent advances leading to a better understanding of the CNS disease processes has placed microglia, the CNS-based resident macrophages, at center stage in this system of active surveillance. Evidence points to microglia cells contributing to the immunosuppressive environment of gliomas and actually promoting tumor growth. Microglia accumulation exists in almost every CNS disease process, including CNS tumors. This article discusses the role of microglia in CNS immunity and highlights key advances made in glioma immunology.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor specific immune regulatory cells play an important role in the pathogenesis of glioma. The mechanisms have not been fully understood yet. It is suggested that placenta growth factor (PlGF) is involved in the generation of immune regulatory cells. This study aims to investigate the role of glioma cell-derived PlGF in the generation of regulatory B cells (Breg). Glioma cells were isolated from surgically removed glioma tissue. Cytokines were measured by enzyme-linked immunosorbent assay, quantitative real time RT-PCR and Western blotting. Immune suppressor functions of Bregs were assessed by T cell proliferation assay. The results showed that glioma cells expressed PlGF, which was increased after a non-specific activation. Naïve B cells captured the PlGF to differentiate into transforming growth factor-β positive Bregs. The Bregs were activated upon exposure to protein extracts of glioma tissue to suppress the CD8+ T cell proliferation and the release of perforin and granzyme B. We conclude that glioma cell-released PlGF can induce Bregs to suppress CD8+ T cell activities.
    The International Journal of Biochemistry & Cell Biology 12/2014; 57. DOI:10.1016/j.biocel.2014.10.005 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma multiforme (GBM) is one of the most lethal human cancers, accounting for about 15% of all primary brain tumors in adults. Tumor-associated microglia/macrophages (TMMs) are a major constituent of the tumor mass and the tumor microenvironment where they support tumor progression. We previously demonstrated that the NAD + utilizing ectoenzyme CD38 regulates microglia activation and that loss of CD38 inhibits glioma progression and extends the survival of glioma-bearing mice. These results indicated that targeting CD38 in the tumor microenvironment may serve as a novel therapeutic approach to treat glioma. To test this hypothesis, we identified small molecules that inhibit CD38 enzymatic activity (NAD + glycohydrolase): the natural anthranoid rhein, its water-soluble tri-potassium salt (K-rhein), and the polyphenol tannic acid (TA). Microglial properties regulated by CD38 (e.g., NO secretion and LPS/IFNγ activation induced cell death) were inhibited in primary microglia treated with rhein in a CD38-dependent manner. Furthermore, wild-type mice intracranially injected with GL261 mouse glioma cells and intranasally treated with K-rhein or TA, exhibited significant reduction in tumor volume and prolonged lifespan compared to vehicle treated mice. On the other hand, these inhibitors had only a modest effect on tumor-bearing Cd38 −/− mice. Taken together, our results demonstrate that small molecule CD38 inhibitors such as K-rhein and TA can target CD38 in the tumor microenvironment and offer a novel and useful strategy for glioma treatment.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuropeptide Y has been shown to inhibit the immunological activity of reactive microglia in the rat cerebral cortex, to reduce N-methyl-D-aspartate current (I NMDA) in cortical neurons, and protect neurons. In this study, after primary cultured microglia from the cerebral cortex of rats were treated with lipopolysaccharide, interleukin-1β and tumor necrosis factor-α levels in the cell culture medium increased, and mRNA expression of these cytokines also increased. After primary cultured cortical neurons were incubated with the lipopolysaccharide-treated microglial conditioned medium, peak I NMDA in neurons increased. These effects of lipopolysaccharide were suppressed by neuropeptide Y. After addition of the neuropeptide Y Y1 receptor antagonist BIBP3226, the effects of neuropeptide Y completely disappeared. These results suggest that neuropeptide Y prevents excessive production of interleukin-1β and tumor necrosis factor-α by inhibiting microglial reactivity. This reduces I NMDA in rat cortical neurons, preventing excitotoxicity, thereby protecting neurons.
    Neural Regeneration Research 05/2014; 9(9):959-67. DOI:10.4103/1673-5374.133140 · 0.23 Impact Factor