Expression of IFN-gamma in Cerebrovascular Endothelial Cells from Aged Mice

Wei, Yaping; Kita, Masakazu; Shinmura, Kazuo; Yan, Xiao-Qun; Fukuyama, Ryuichi; Fushiki, Shinji; Imanishi, Jirô

doi:10.1089/107999000312342

Cited by 50 publications

(31 citation statements)

References 29 publications

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“…3, 4). The primary sources of IFN-g in the inflamed brain are Th1 and NK cells, DCs, and macrophages, but it has also been shown that low levels of IFN-g can be produced by astrocytes, fibroblasts, cerebrovascular endothelial cells, and microglia itself in the healthy CNS (36)(37)(38). Microglia-mediated Treg induction is cell-cell contact-dependent, Ag-specific (dependent on MHC II and cognate peptide), and requires intermediate levels of CD40 and CD86 on the microglia site.…”

Section: Discussionmentioning

confidence: 99%

Microglial Activation Milieu Controls Regulatory T Cell Responses

Ebner

Brandt

Thiele

et al. 2013

The Journal of Immunology

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Although mechanisms leading to brain-specific inflammation and T cell activation have been widely investigated, regulatory mechanisms of local innate immune cells in the brain are only poorly understood. In this study, to our knowledge we show for the first time that MHC class II+CD40dimCD86dimIL-10+ microglia are potent inducers of Ag-specific CD4+Foxp3+ regulatory T cells (Tregs) in vitro. Microglia differentially regulated MHC class II expression, costimulatory molecules, and IL-10 depending on the amount of IFN-γ challenge and Ag dose, promoting either effector T cell or Treg induction. Microglia-induced Tregs were functionally active in vitro by inhibiting Ag-specific proliferation of effector T cells, and in vivo by attenuating experimental autoimmune encephalomyelitis disease course after adoptive transfer. These results indicate that MHC class II+CD40dimCD86dimIL-10+ microglia have regulatory properties potentially influencing local immune responses in the CNS.

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Section: Discussionmentioning

confidence: 99%

Microglial Activation Milieu Controls Regulatory T Cell Responses

Ebner

Brandt

Thiele

et al. 2013

The Journal of Immunology

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“…Although T cells are the main source of IFN␥ throughout the body, these cells are relatively restricted from entering the healthy brain. However, it has been shown that low IFN␥ levels can be produced by nonimmune or non-inflammatory cells, such as astrocytes, fibroblasts, and cerebrovascular endothelial cells (Rady et al, 1995;De Simone et al, 1998;Wei et al, 2000), which comprise the resident cells of the SVZ. Our PCR analysis (data not shown) reveals that IFN␥ is present in both primary SVZ tissue and untreated neurosphere cultures.…”

Section: Discussionmentioning

confidence: 99%

“…By mimicking the inflammatory scenario in vivo, Butovsky et al (2006) have shown that cultured microglia exposed to lysophosphatidic acid and stimulated with IFN␥ support neurogenesis. Nevertheless, to date, no evidence exists to demonstrate that IFN␥ plays a role in neurogenesis in the non-inflammatory brain, although it has been shown that low levels of IFN␥ can be produced by astrocytes, fibroblasts, and cerebrovascular endothelial cells under normal conditions (Rady et al, 1995;De Simone et al, 1998;Wei et al, 2000). In the present study, we therefore investigated the effect of IFN␥ on NP activity and neurogenesis.…”

Section: Introductionmentioning

confidence: 96%

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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Although a number of growth factors have been shown to be involved in neurogenesis, the role of inflammatory cytokines remains relatively unexplored in the normal brain. Here we investigated the effect of interferon gamma (IFN␥) in the regulation of neural precursor (NP) activity in both the developing and the adult mouse brain. Exogenous IFN␥ inhibited neurosphere formation from the wild-type neonatal and adult subventricular zone (SVZ). More importantly, however, these effects were mirrored in vivo, with mutant mice lacking endogenous IFN␥ displaying enhanced neurogenesis, as demonstrated by an increase in proliferative bromodeoxyuridinelabeled cells in the SVZ and an increased percentage of newborn neurons in the olfactory bulb. Furthermore, NPs isolated from IFN␥ null mice exhibited an increase in self-renewal ability and in the capacity to produce differentiated neurons and oligodendrocytes. These effects resulted from the direct action of IFN␥ on the NPs, as determined by single-cell assays and the fact that nearly all the neurospheres were derived from cells positive for major histocompatibility complex class I antigen, a downstream marker of IFN␥-mediated activation. Moreover, the inhibitory effect was ameliorated in the presence of SVZ-derived microglia, with their removal resulting in almost complete inhibition of NP proliferation. Interestingly, in contrast to the results obtained in the adult, exogenous IFN␥ treatment stimulated neurosphere formation from the embryonic brain, an effect that was mediated by sonic hedgehog. Together these findings provide the first direct evidence that IFN␥ acts as a regulator of the active NP pool in the non-inflammatory brain.

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“…This cytokine is known to play a role in preventing infectious diseases and promoting a host response to tumors, but it has not been, to our knowledge, associated with aging of the epidermis (108,109). Wei and colleagues (110) have presented evidence indicating that IFN-␥ may play a role in age-associated changes that take place in mouse brain since they have found increased expression of IFN-␥ mRNA and protein during aging. Using immunofluorescence they traced the source of IFN-␥ to the cerebrovascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%