Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis

Luo, Jian; Ho, Peggy P.; Buckwalter, Marion S.; Hsu, Tiffany; Lee, Lowen Y.; Zhang, Hui; Kim, Dae‐Kee; Kim, Seong‐Jin; Gambhir, Sanjiv S.; Steinman, Lawrence; Wyss‐Coray, Tony

doi:10.1172/jci31763

Cited by 108 publications

(117 citation statements)

References 57 publications

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“…Furthermore, TGF-b1 pathway blockers efficiently blocked epileptogenesis in BBB breakdown and albumin models of epilepsy in mice and rats (11,16). Although TGF-b1 is a well-characterized immunoregulatory cytokine (19,20,25,(31)(32)(33)(34), it can also exert autoimmunity, glial activation, and brain inflammation (22,23,35,36). In the present study, we demonstrate that glial exposure to TGF-b1 induces a rapid and robust IL-6 upregulation at both the mRNA and protein levels.…”

Section: Discussionsupporting

confidence: 57%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6–treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1–induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte–neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

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Section: Discussionsupporting

confidence: 57%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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“…61 Likewise, TGF-␤ has recently been shown to promote EAE. 62 These novel findings suggest that inflammatory cytokines may act as a doubleedged sword, being both immunopromotive and immunosuppressive, depending on the phase of disease. 51,52 In conclusion, our findings suggest that ICAM-5 is involved in the immune privilege of the brain and could be a useful anti-inflammatory agent for the treatment of various inflammatory brain diseases.…”

Section: Discussionmentioning

confidence: 99%

Shedded neuronal ICAM-5 suppresses T-cell activation

Tian

Lappalainen

Autero

et al. 2008

Blood

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IntroductionInflammation is generally regarded as harmful to the brain because local and infiltrated immune cells, as well as proinflammatory cytokines, exacerbate the neuronal damage in various neurodegenerative and autoimmune diseases. 1-4 Healthy brain prevents the penetration of lymphocytes into the brain parenchyma and also down-regulates the activity of infiltrated lymphocytes. 5,6 Nevertheless, the brain is neither isolated nor passive in its interactions with the immune system. 7 Once neuronal damage occurs, T cells and antigen-presenting cells (APC) accumulate at lesion sites, with concomitant increased expression of the major histocompatibility complex (MHC) and costimulatory molecules, which are necessary for T-cell activation. [8][9][10][11] It is perceivable that a strict control of the activation of T cells is important to ameliorate their harmful effects on neurons.Optimal activation of T cells by APCs requires at least 2 signals. The first is elicited through recognition of the MHC-peptide complex by T-cell receptor (TCR), and the second is provided by the costimulatory molecules via interaction with their respective receptors on T cells. Costimulatory molecules are key factors required for full activation of the primed T cells, especially the naive T cells. Without costimulation, the primed T cells will turn into unresponsiveness or anergy. [12][13][14] Among the costimulatory molecules, B7 (CD80 or 86), CD40, and intercellular adhesion molecule (ICAM)-1 have all been detected at inflammatory sites in brain. 8,10,11 ICAM-1 is known to promote the activation of T cells through binding to its integrin receptor lymphocyte function associated antigen-1 (LFA-1, ␣L␤2, CD11a/CD18). 15-17 LFA-1 and ICAM-1 are involved in the formation of the adhesion ring junction or the peripheral supramolecular activation complex at the immunologic synapse between T cells and APCs. 18,19 The ICAMs belong to the immunoglobulin (Ig) superfamily, and 5 ICAM members (ICAM-1-5) have been identified. 20,21 In brain, ICAM-1 is expressed in endothelial, epithelial, and glial cells. 22 By contrast, ICAM-5 (telencephalin) has been shown to be expressed only in the telencephalic neurons, and its synthesis takes place mainly after birth. 23 Structurally, ICAM-5 is a type I membrane protein with 9 Ig-like domains in the extracellular part, a short transmembrane region, and a cytoplasmic tail. 23,24 ICAM-5 has been shown to bind to LFA-1 [25][26][27] and to regulate the morphology of microglia. 28 In conditions of brain ischemia, 29 epilepsy, 30,31 and encephalitis, 32 the soluble form of ICAM-5 (sICAM-5) has been detected in physiologic fluids.Because of its specific expression pattern, and also being a ligand for LFA-1, it is crucial to establish whether ICAM-5 can act as a costimulatory molecule for T cells, as ICAM-1 does, and whether it regulates T-cell activity during brain inflammation. Here, we find that, in contrast to ICAM-1, the expression of ICAM-5 is not up-regulated by the cytokines tumor necrosis factor (TNF) and int...

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“…Silencing of TGF-BR1 on microglia promoted neuroinflammation and neuronal damage in a model of Parkinson's disease (46). However, early astrocyte production of TGF-β1 appears to establish a permissive environment for autoimmunity and enhanced inflammation in EAE (49). In a rat model of ischemic stroke, TGFBR1 was upregulated on microglia (47), although no functional role was investigated.…”

Section: +/Gfpmentioning

confidence: 99%

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

Taylor

Chang

Goods

et al. 2016

Journal of Clinical Investigation

213

195

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Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis

Cited by 108 publications

References 57 publications

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Shedded neuronal ICAM-5 suppresses T-cell activation

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

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