Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice

Loo, Geert; Lorenzi, Rossana De; Schmidt, Hauke; Huth, Marion; Mildner, Alexander; Schmidt-Supprian, Marc; Lassmann, Hans; Prinz, Marco; Pasparakis, Manolis

doi:10.1038/ni1372

Cited by 188 publications

(148 citation statements)

References 45 publications

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“…Furthermore NF-kB inhibition has antiproliferative and pro-apoptotic effects on lymphoid cells. The effects of selective absence of NF-kB in CNS resident cells in EAE has been recently investigated by inducible knockdown of IKK2 [36]. Consistent with the inhibitory effect of bortezomib on the activation of NF-kB in different tumor cells [20,23], we here demonstrate that the therapeutic effect of bortezomib in EAE is accompanied by inhibition of NF-kB activation in spleen and spinal cords in vivo.…”

Section: Discussionsupporting

confidence: 85%

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

et al. 2008

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Multiple sclerosis (MS) is a detrimental disease of the central nervous system (CNS) leading to long-term disability. In the course of animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), we find enhanced activity of proteasome subunits b1i, b2, b2i and b5 in the CNS. We demonstrate that pharmacological inhibition of the proteasome by bortezomib ameliorates experimental autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment with reduced numbers of T-cells secreting proinflammatory cytokines. The anti-inflammatory effect of proteasome inhibition was accompanied by reduced NF-jB activity in the CNS and lymphoid organs. The combined inhibition of proteasomes and lysosomal proteases involved in major histocompatibility complex II antigen presentation further improved therapeutic efficacy. We suggest proteasome inhibition alone or in combination with inhibition of lysosomal proteases as a novel therapeutic strategy against inflammation-induced neurodegeneration in the CNS. We demonstrate the impact of the proteasome and lysosomal proteases on development of autoimmunity.

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Section: Discussionsupporting

confidence: 85%

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

et al. 2008

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“…Finally, central nervous system (CNS)-specific ablation of Ikbkg leads to decreased expression of key mediators involved in CNS inflammation (cytokines, chemokines, vascular cell adhesion molecule-1, etc). In that case the absence of Ikbkg ameliorates the disease pathology in the mouse model of autoimmune encephalomyelitis, suggesting that the expression of the IKK subunit is essential to create a proinflammatory condition of CNS [van Loo et al, 2006].…”

Section: Mouse Modelsmentioning

confidence: 99%

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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Communicated by Andrew O.M. WilkieMutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP-and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (465%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families. Hum Mutat 29(5), [595][596][597][598][599][600][601][602][603][604] 2008.

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“…Experimental evidence suggests that early astrocyte activation can promote EAE. NF-kB-driven astrocyte activation contributes to a more severe course of EAE characterized by an increased expression of proinflammatory cytokines and chemokines as well as increased demyelination (2,3). This astrocytic NF-kB activation is critically regulated by IL-17-mediated activation of Act1; in the absence of astrocytic Act1 signaling, mice are largely protected from EAE and CD4 T cell infiltration to the spinal cord (4,5).…”

mentioning

confidence: 99%

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Haroon

Drögemüller

Händel

et al. 2011

The Journal of Immunology

109

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Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein35–55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/fl mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130fl/fl mice, whereas gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/fl mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130fl/fl mice resulted in a reduction of CNS regulatory Foxp3+ CD4 T cells and an increase of IL-17–, IFN-γ–, and TNF-producing CD4 as well as IFN-γ– and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130– Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130–STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130–Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130–STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.

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Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice

Cited by 188 publications

References 45 publications

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

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