Microglia derived IL-6 suppresses neurosphere generation from adult human retinal cell suspensions

Balasubramaniam, Balini; Carter, Debra A; Mayer, Eric; Dick, Andrew D.

doi:10.1016/j.exer.2009.06.019

Cited by 35 publications

(26 citation statements)

References 69 publications

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“…2c). A substantial proportion of microglia from adult human retinal explants express CD11c 23 and here we provide in vivo data showing that CD11c + cells in STAT1-deficient mice secrete markedly reduced amounts of IL-27 and this observation correlates with enhanced expansion of Th17 cells in blood and retina (Fig. 4) and development of a more severe form of uveitis by the STAT1KO mice (Fig.…”

Section: Discussionsupporting

confidence: 59%

“…In a recent study, > 50% of microglia from adult human retinal explants express CD11c. 23 However, because the number of the CD11c + cells in the mouse retina is low, we used CD11c + cells generated from bone marrow of WT and STAT1KO mice to examine whether the secretion of IL-27 by CD11c + microglia cells is mediated through STAT1. Phenotypic characterization of the CD11c + cells is shown in Fig.…”

Section: Stat1 Is Required For the Production Of Il-27 And Anti-inflamentioning

confidence: 99%

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Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

Lee

Amadi-Obi

et al. 2011

Immunology

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Summary Neuronal or photoreceptor deficit observed in uveitis and multiple sclerosis derives in part from inability to control inflammatory responses in neuroretina or brain. Recently, IL‐27 was found to play a role in suppressing experimental autoimmune uveitis and experimental autoimmune encephalomyelitis, two animal models that share essential pathological features of human uveitis and multiple sclerosis, respectively. However, the mechanism by which interleukin‐27 (IL‐27) inhibits central nervous system (CNS) inflammation is not clear. In this study we have investigated mechanisms that mitigate or curtail intraocular inflammation (uveitis) and examined whether inhibitory effects of IL‐27 are mediated locally by neuroretinal cells or by regulatory T cells. We show here that microglia cells in the neuroretina constitutively secrete IL‐27 and its expression is up‐regulated during uveitis. We further show that photoreceptors constitutively express IL‐27 receptor and respond to IL‐27 signalling by producing anti‐inflammatory molecules, IL‐10 and suppressor of cytokine signalling 1 (SOCS1) through signal transducer and activator of transcription 1 (STAT1) ‐dependent mechanisms. Moreover, STAT1‐deficient mice produced reduced amounts of IL‐27, IL‐10 and SOCS1 and developed more severe uveitis. Surprisingly, IL‐10‐producing regulatory T cells had marginal roles in suppressing uveitis. These results suggest that suppression of intraocular inflammation might be mediated through endogenous production of IL‐27 and IL‐10 by retinal cells, whereas SOCS proteins induced by IL‐27 during uveitis may function to protect the neuroretinal cells from the toxic effects of pro‐inflammatory cytokines. Targeted delivery of IL‐27 into immune privileged tissues of the CNS may therefore be beneficial in the treatment of CNS inflammatory diseases, such as uveitis and multiple sclerosis.

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Section: Discussionsupporting

confidence: 59%

Section: Stat1 Is Required For the Production Of Il-27 And Anti-inflamentioning

confidence: 99%

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

Lee

Amadi-Obi

et al. 2011

Immunology

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“…Accordingly, the white matter specific increase in CD68 expression may correlate to the histologically observed necrosis, a process necessitating phagocytosis and debris removal. Furthermore, enhanced phagocytic capacity is associated with microglial activation(75) that in turn produces a number of pro-inflammatory cytokines (76–78), which may contribute to a sustained pro-inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

et al. 2017

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Andrews, R. N., Metheny-Barlow, L. J., Peiffer, A. M., Hanbury, D. B., Tooze, J. A., Bourland, J. D., Hampson, R. E., Deadwyler, S. A. and Cline, J. M. Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat. Res. 187, 599–611 (2017). Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6–11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/ microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman’s test), with effects most prominent within cerebral white matter.

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“…In addition, IL-6 has been found to regulate survival of differentiated neurons and the development of astrocytes [36,37]. Some in-vitro studies show IL-6 release by activated microglia is a key inhibitor of neurogenesis by approximately 50%; others show IL-6 promoting differentiation of neural stem cells (NSCs) [10,80-82]. NSCs derived from rodent spinal cord show that IL-6 induces NSC proliferation via the JAK2/STAT3 and MAPK pathways [83].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Baune

Konrad

Grotegerd

et al. 2012

J Neuroinflammation

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BackgroundCytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated.MethodologyIn a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.Principal findings/resultsIn a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses.Conclusions/significanceThese findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.

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Microglia derived IL-6 suppresses neurosphere generation from adult human retinal cell suspensions

Cited by 35 publications

References 69 publications

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

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