Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination

Emery, Ben; Cate, Holly S.; Marriott, Mark; Merson, Tobias D.; Binder, Michele D.; Snell, Cameron; Soo, Pik Ying; Murray, Simon S.; Croker, Ben A.; Zhang, Jian Guo; Alexander, Warren S.; Cooper, Helen; Butzkueven, Helmut; Kilpatrick, Trevor J.

doi:10.1073/pnas.0602574103

Cited by 72 publications

(64 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In good correlation with the data on LIF treatment, cuprizone-induced demyelination in LIF Ϫ/Ϫ mice resulted in a more pronounced oligodendrocyte loss (43). Moreover, Ab-mediated neutralization of LIF doubled the extent of oligodendrocyte loss in an EAE model (19).…”

Section: Discussionsupporting

confidence: 66%

Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation

Linker

Kruse

Israel

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

The neurotrophic cytokines ciliary neurotrophic factor and leukemia inhibitory factor (LIF) play a key role in neuronal and oligodendrocyte survival and as protective factors in neuroinflammation. To further elucidate the potential of endogenous LIF in modulating neuroinflammation, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LIF knockout mice (LIF−/− mice). In the late phase of active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, LIF−/− mice exhibited a markedly milder disease course. The inflammatory infiltrate in LIF−/− mice was characterized by an increase in neutrophilic granulocytes early and fewer infiltrating macrophages associated with less demyelination later in the disease. In good correlation with an effect of endogenous LIF on the immune response, we found an Ag-specific T cell-priming defect with impaired IFN-γ production in LIF−/− mice. On the molecular level, the altered recruitment of inflammatory cells is associated with distinct patterns of chemokine production in LIF−/− mice with an increase of CXCL1 early and a decrease of CCL2, CCL3, and CXCL10 later in the disease. These data reveal that endogenous LIF is an immunologically active molecule in neuroinflammation. This establishes a link between LIF and the immune system which was not observed in the ciliary neurotrophic factor knockout mouse.

show abstract

Section: Discussionsupporting

confidence: 66%

Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation

Linker

Kruse

Israel

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…These findings indicate that SOCS-3 represses the ability of reactive astrocytes to promote healing after spinal cord injury by blocking STAT-3 activation. Conditional deletion of SOCS-3 in oligodendrocytes enhanced the protective effect of LIF on cuprizone-induced demyelination (62), demonstrating that SOCS-3 expression in oligodendrocytes attenuates the beneficial effects of LIF in limiting demyelination. In contrast, targeted expression of SOCS-1 in oligodendrocytes protects them against the injurious effects of IFN-␥ (63).…”

Section: Discussionmentioning

confidence: 98%

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

Qin¹,

Roberts²,

Niyongere³

et al. 2007

The Journal of Immunology

155

145

View full text Add to dashboard Cite

Immunological activation of macrophages/microglia within the CNS leads to the production of cytokines and chemokines that ultimately impact on glial and neuronal function. Suppressor of cytokine signaling (SOCS) proteins are negative regulators of adaptive and innate immune responses. Our previous studies demonstrated that SOCS-3 attenuates macrophage/microglial activation in vitro, suggesting that SOCS-3 may exert beneficial effects for immune-mediated CNS diseases in vivo. In this study, we describe LPS as a potent inducer of SOCS-3 transcription and expression in macrophages/microglia. An analysis of the SOCS-3 promoter indicates that AP-1 and IFN-γ activation sequence (GAS) elements are involved in LPS-induced SOCS-3 transcription. LPS-induced SOCS-3 expression was diminished in IL-10-deficient macrophages at later time points, indicating the involvement of endogenous IL-10 in this response. Blocking STAT-3 expression and activation using STAT-3 small interfering RNA reduced LPS-induced SOCS-3 gene expression. LPS activated the MAPK-ERK1/2, JNK, and p38 pathways that, in addition to STAT-3, were also involved in LPS-induced SOCS-3 expression. LPS treatment of cells led to the acetylation of histones H3 and H4 on the SOCS-3 promoter and the recruitment of STAT-3, c-Jun, c-Fos, CREB-binding protein, p300, and RNA polymerase II to the endogenous SOCS-3 promoter in a time-dependent manner. These results indicate that LPS-induced MAPK activation, the production of endogenous IL-10, and STAT-3 activation play critical roles in SOCS-3 expression, which provides for feedback attenuation of cytokine-induced immune and inflammatory responses in macrophages and microglia.

show abstract

“…1A). We used a 1.94 kb MBP promoter that had previously been shown to direct transgene expression specifically to the mature oligodendrocyte lineage (Gow et al, 1992;Wrabetz et al, 1998;Emery et al, 2006). Eighteen germline-transmitting MBP-DTR transgenic founders were identified by Southern blot (Fig.…”

Section: Mbp-dtr Mice Express Dtr Exclusively In Oligodendrocytes In mentioning

confidence: 99%

Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination

Oluich

Stratton

Xing

et al. 2012

Journal of Neuroscience

108

View full text Add to dashboard Cite

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ϳ26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted.

show abstract

Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination

Cited by 72 publications

References 37 publications

Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation

Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination

Contact Info

Product

Resources

About