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Tyrosine kinase 2 (TYK2), a key part of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, plays an integral role in the differentiation and immune responses of intrinsic immune cells and regulates the mediation of cytokines. TYK2 leads to inflammatory cascade responses in the pathogenesis of immune-mediated inflammatory diseases (IMIDs), especially psoriasis. Small-molecule TYK2 inhibitors are considered to be an effective strategy for modulating psoriasis. Here, we attempt to review the pro-inflammatory mechanisms of the JAK-STAT signaling pathway, the regulatory roles of TYK2 in the pathogenesis of psoriasis, and provide updates on ongoing and recently completed trials of TYK2 inhibitors.

There are four JAK subtypes: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Small molecule Janus tyrosine kinase (JAK) inhibitors can inhibit a variety of pro-inflammatory cytokines. Baricitinib is the first generation of JAK1/2 inhibitor targeting the ATPase of JAK, which blocks the intracellular transmission of cytokines through JAK-STATs. Thus far, it has been approved for the treatment of rheumatoid arthritis (RA); however, an increasing number of studies have suggested that baricitinib can be used to treat dermatological diseases, such as atopic dermatitis (AD), psoriasis, vitiligo, and alopecia areata. Baricitinib can be a new choice for the treatment of dermatological diseases, which cannot be treated with conventional drugs. We reviewed the application, efficacy, side effects, precautions, limitations and prospect of baricitinib in atopic dermatitis, psoriasis, vitiligo and alopecia areata (AA) in recent 5 years including clinical trials and case reports. Among them, the application in the field of alopecia areata is the most encouraging, and we reviewed the mechanism in detail.

Contains fulltext : 196332.pdf (Publisher’s version ) (Closed access) Reducing the activities of the pro-inflammatory cytokine IL-17 is an effective treatment strategy for several chronic autoimmune disorders. Rho-associated coiled-coil containing kinase 2 (ROCK2) is a member of the serine-threonine protein kinase family that regulates IL-17 secretion in T cells via signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. We reported here that the selective ROCK2 inhibitor KD025 significantly reduced in vitro production of IL-17 in unfractionated human peripheral blood mononuclear cells (PBMCs) stimulated with the dectin-1 agonist Candida albicans. C. albicans induced IL-17 was reduced by 70% (p < 0.0001); a similar reduction (80%) was observed in PBMC stimulated with the Toll-like receptor 2 agonist Staphylococcus epidermidis (p < 0.0001). Treatment of PBMC with KD025 was not associated with a reduction in IL-1beta, IL-6 or IL-1alpha levels; in contrast, a 1.5 fold increase in the level of IL-1 receptor antagonist (IL-1Ra) was observed (p < 0.001). KD025 down-regulated C. albicans-induced Myosin Light Chain and STAT3, whereas STAT5 phosphorylation increased. Using anti-CD3/CD28 activation of the TCR, KD025 similarly suppressed IL-17 independent of a reduction in IL-1beta. Thus, ROCK2 directly regulates IL-17 secretion independent of endogenous IL-1 and IL-6 supporting development of selective ROCK2 inhibitors for treatment of IL-17-driven inflammatory diseases.

SFRP1 acts as a well-established inhibitory regulator of the Wnt signaling pathway, whose polymorphisms have been demonstrated to be associated with the risk of inflammation, infection as well as cancer. We verified the hypothesis that single nucleotide polymorphisms (SNPs) within SFRP1 gene are associated with susceptibility and clinical characteristics of tuberculosis disease in a Chinese Han population.Six candidate SNPs were genotyped using MassARRAY method in a case-control design (260 tuberculosis patients and 252 healthy controls). A comprehensive analysis of single locus including the genotypic, allelic frequencies and the genetic models, haplotypic construction as well as gene-gene interaction was conducted to investigate the relationships between SNPs and TB. Significant SNPs were further interrogated in relation to TB clinical features and host inflammatory status.Genotype frequencies of rs4736958 and rs7832767 within SFRP1 gene were significantly different (p=0.011, p=0.008, respectively) between tuberculosis group and control group. Subjects carrying C allele for rs4736958 showed a decreased tuberculosis risk (OR=0.66, 95% CI=0.51-0.87, p=0.003), whereas individuals carrying rs7832767 T allele had a significant increased risk in tuberculosis susceptibility (OR=1.32, 95% CI=1.01-1.74, p=0.046). Genetic model analysis revealed that dominant, co-dominant and recessive models of rs4736958 were associated with decreased susceptibility to tuberculosis (p all0.05), while the recessive and co-dominant models of rs7832767 were related to significantly increased risk for tuberculosis (p all0.05). There was a reduced tuberculosis risk in association with the haplotype CC (representing rs3242 and rs4736958) of SFRP1 (OR=0.73, 95% CI=0.56-0.96, p=0.026). Further stratification analysis indicated that TB patients with genotype CT for rs4736958 were associated with higher CRP concentrations, and heterozygous patients (CT genotype) of rs7832767 trended towards greater ESR levels.SNPs rs4736958 and rs7832767 of SFRP1 gene were significantly associated with tuberculosis susceptibility and might influence the expression levels of inflammatory markers of tuberculosis patients in a Chinese Han population.

Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Conduction block in demyelinated axons underlies early neurological symptoms, but axonal transection and neuronal loss are believed to be responsible for more permanent chronic deficits. Several therapies are approved for treatment of relapsing-remitting MS, all of which are immunoregulatory and clinically proven to reduce the rate of lesion formation and exacerbation. However, existing approaches are only partially effective in preventing the onset of disability in MS patients, and novel treatments to protect myelin-producing oligodendrocytes and enhance myelin repair may improve long-term outcomes. Studies in vivo in genetically modified mice have assisted in the characterization of mechanisms underlying the generation of neuropathology in MS patients, and have identified potential avenues for oligodendrocyte protection and myelin repair. However, no treatments are yet approved that target these areas directly, and in addition, the relationship between demyelination and axonal transection in the lesions of the disease remain unclear. Here, we review translational research targeting oligodendrocyte protection and myelin repair in models of autoimmune demyelination, and their potential relevance as therapies in MS patients.

Current therapies for multiple sclerosis target inflammation but do not directly address oligodendrocyte protection or myelin repair. The gp130 family cytokines ciliary neurotrophic factor, leukemia inhibitory factor, and IL-11 have been identified as oligodendrocyte growth factors, and IL-11 is also strongly immunoregulatory, but their underlying mechanisms of action are incompletely characterized. In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag-presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3. Focal demyelinating lesions induced in cerebral cortices of IL-11Rα−/− mice using stereotactic microinjection of lysolecithin were larger than in controls, and remyelination was delayed. In IL-11Rα−/− mice, lesions displayed extensive oligodendrocyte loss and axonal transection, and increased infiltration by inflammatory cells including CD11c+ DCs, CD3+ lymphocytes, and CD11b+ phagocytes. In oligodendrocyte progenitor cell (OPC) cultures, IL-11 restricted caspase 9 activation and apoptosis, and it increased myelination in OPC-neuron cocultures. Importantly, siRNA inhibition of Stat1 enhanced the antiapoptotic effects of IL-11 on OPCs, but IL-11 induced apoptosis in the presence of Stat3 silencing. In contrast, IL-11 augmented caspase activation and apoptosis in cultures of CD11c+ DCs, but not in CD11b+ or CD3+ cells. Inhibition of Stat3 exacerbated the proapoptotic effects of IL-11 on DCs, whereas they were ablated in Stat1−/− cultures. Collectively, these findings reveal novel mechanisms underlying the actions of a neuroprotective and immunoregulatory member of the gp130 cytokine family, suggesting avenues to enhance oligodendrocyte viability and restrict CNS inflammation in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology. Conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory, and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability in MS patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes and reduce the rate of axonal transection. Studies in genetically modified animals have improved our understanding of mechanisms underlying CNS pathology in MS models, and have identified pathways that regulate oligodendrocyte viability and myelin repair. However, although clinical trials are ongoing, many have been unsuccessful and no treatments are yet approved that target these areas in MS. In this review, we examine avenues for oligodendrocyte protection and endogenous myelin repair in animal models of de- and remyelination, and their relevance as therapeutics in human patients.

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

Targeted inhibition of Rho-associated kinase 2 (ROCK2) down-regulates pro-inflammatory T-cell response, while increasing the regulatory arm of immune response in animals models of autoimmunity and T helper 17 (Th17)-skewing human cell culture in vitro. We conducted a Phase 2, open-label, dose-finding study to evaluate the safety, tolerability, and activity of selective ROCK2 inhibitor, KD025, in subjects with Psoriasis Vulgaris who failed first-line therapy (NCT02317627 at ClinicalTrials.gov). Here, we report that oral administration of KD025 reduces Psoriasis Area and Severity Index (PASI) scores in 85% of patients completing the study, with minimal side effects. In the 400 mg QD and 200 mg BID cohorts 42% and 71% of patients respectively achieved at least a 50% decrease in PASI score (PASI 50) after three month of treatment. KD025 treatment reduced levels of both IL-17 and IL-23, but no IL-6 and TNF-a in the peripheral blood of clinical responders, whereas IL-10 levels were increased at the end of the study. The clinical improvement and changes in cytokine levels were associated with decreased epidermal thickness, T-cell infiltration and down-regulation of key molecules implicated in the regulation of the Th17 pathway, such as ROCK2, pSTAT3, RORgt and IRF4 in the skin. Collectively, these data demonstrate that orally available selective ROCK2 inhibitor down-regulates Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

Rho-associated kinase 2 (ROCK2) was recently shown to be implicated in regulation of IL-17 and IL-21 secretion in both mice and humans via down-regulation of STAT3 phosphorylation and subsequent transcription activity. Here we report that the ROCK2, but not ROCK1 protein binds phosphorylated-STAT3 (pSTAT3) in both cytoplasmic and nuclear compartments in human CD4+ T cells during T helper 17 (TH17)-skewing activation. The interaction of ROCK2 with pSTAT3 was partially abrogated by treatment of cells with selective ROCK2 inhibitor suggesting that ROCK2 kinase activity is required for formation of JAK-STAT complex and STAT3 phosphorylation. Further analysis by chromatin-immunoprecipitation sequencing (ChIP-seq) revealed that ROCK2 binding is significantly enriched toward promoter regions and peaks at transcription start sites (TSS) relative to genomic DNA. Moreover, 60–70% of ROCK2 and STAT3 peaks are overlapped genome-wide and co-localized to several key genes that control TH17 and T follicular helper (TFH) cell functions. Specifically, the binding of ROCK2 and STAT3 to the IRF4 and Bcl6 genes was validated by ChIP-qPCR analysis performed in human CD4+ T cells activated by TH17-skewing conditions. Finally, siRNA-mediated inhibition of STAT3 attenuated ROCK2 binding to the IRF4 and Bcl6 promoters indicating the critical role of STAT3 in the recruitment of ROCK2 to chromatin and ROCK2-mediated regulation of TH17/TFH gene transcription. Together, the present work provides previously unidentified insights into the molecular mechanism of specific involvement of ROCK2 isoform in regulating STAT3 phosphorylation and transcriptional activity in TH17-driven autoimmune responses.

In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb−/− embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3−/− mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

Type 2 diabetes mellitus (T2DM) has been gradually considered as a micro- inflammatory disease. To explore the significance of peripheral CD4(+) regulatory T cells and CD4(+) effector T cells in T2DM, we analyzed inflammation, humoral and cellular immune state in patients with T2DM.118 patients with T2DM without complications and 116 healthy volunteers were included. Serum C-reactive protein (CRP), Complement 3 (C3), Complement 4 (C4), IgG, IgA, IgM, plasma sIL-2 R and peripheral T lymphocyte subsets (including CD4(+)CD25(high) regulatory T cells (Treg) and CD4(+)CD25(low+median) effector T cells (Teff)) were analyzed by rate nephelometry immunoassay, chemiluminescence immunoassay and flow cytometry, respectively.(1) micro-inflammation state in T2DM: Serum CRP, C3, IgA and plasma sIL-2 R were all significantly higher in T2DM than those in healthy control (HC) (all P0.05). (2) Disturbance of cellular immune in T2DM: Compared with HC, the percentage of peripheral CD3(+)CD4(+)T cells and ratio of CD3(+)CD4(+)T cells to CD3(+)CD8(+)T cells in T2DM were both significantly increased (P0.05); and the percentage of peripheral CD4(+)CD25(+)T cells, Teff cells increased (P0.05), Treg cells strikingly decreased in T2DM (P0.05). A positive correlation between sIL-2R levels and peripheral CD4(+)CD25(+)T cells or Teff cell percentages, as well as a negative correlation between plasma sIL-2 R levels and serum HDL, LDL or CHOL levels in T2DM were shown (all P0.05).Micro-inflammation state in T2DM was characterized by increased sIL-2 R, elevated CD3(+)CD4(+)T cells and the imbalance of Treg cells and Teff cells, which as one of the pathogeneses took part in inflammation reaction in T2DM.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination., During the development of white matter in the central nervous system, the transcription factor Klf6 coordinates pro-myelinating effects of gp130-Stat3 signaling, and promotes oligodendrocyte differentiation in part via control of nuclear trafficking., Author Summary Myelin, a membranous sheet that surrounds the axons of neurons and facilitates the transmission of nerve impulses, is formed by oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). Failure to myelinate, or demyelination, produces the symptoms of serious diseases such as leukodystrophies and multiple sclerosis. This study identifies a novel and essential regulator of myelin formation in the CNS: the transcriptional activator Krüppel-like factor-6 (Klf6). We show that Klf6 acts as a control point through which pro-myelinating signals regulate the development of oligodendrocytes from oligodendrocyte progenitor cells. Growth factors of the gp130 family are known to promote differentiation and survival of oligodendrocytes, via activation of the transcription factor Stat3, but the mechanistic details of how they do it remain unclear. Our findings show that Klf6 is induced in oligodendrocyte progenitors by gp130 growth factors, and promotes differentiation. Furthermore, oligodendrocyte progenitor cells in which Klf6 is inactivated do not mature, fail to form myelin, and eventually die. We also uncover that upon gp130 signaling, Klf6 activates the nuclear import factor importin-α5 (Impα5), a key controller of trafficking into the nucleus in the CNS. Notably, inactivation of Impα5 recapitulates the features of silencing Klf6, whereas Impα5 expression can partially rescue differentiation in Klf6-deficient oligodendrocyte progenitors. Finally, inactivation of Stat3 in oligodendrocyte progenitors produces defective Klf6 and Impα5 expression and myelination failure, strongly resembling the features produced by Klf6 inactivation. Collectively, these results establish a connection between gp130-Stat3 signaling and importin-based control of nuclear trafficking, which is essential for myelination in the CNS, and places Klf6 as a key coordinator of these events.

Objective: Laquinimod is an orally administered CNS-active immunomodulator currently in phase III clinical trials for therapy of relapsing remitting multiple sclerosis (RRMS). Data show that RRMS patients show beneficial effects of laquinimod 0.6mg on clinical disease activity as evidenced by slowing of the progression of disability, reducing the rate of MRI-measured brain volume loss, and reducing relapse rate. The current work examines the mechanisms underlying these effects. Background Laquinimod crosses the blood-brain barrier and enters the CNS, thus in addition to peripheral effects it may act directly on CNS-resident lineages including oligodendrocytes, microglia and astrocytes. Increasing evidence implicates reactive astrocytes as critical regulators of CNS inflammation and repair in MS. Design/Methods: Here, we report that laquinimod profoundly impacts proinflammatory gene expression in a human in vitro model of reactive astrogliosis. Results: Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in RRMS, and in primary human astrocyte cultures it strongly induced inflammatory factors including cytokines, chemokines and reactive nitrogen species. Importantly, at therapeutic concentrations, laquinimod abrogated IL-1β-induced induction of cytokines including tumor necrosis factor-α (TNFα) and IL-6, and inducible nitric oxide synthase. Laquinimod also differentially regulated IL-1β-induced expression of CXC and CC chemokines, suggesting that it acts as an immunomodulator rather than an immunosuppressant in astrocyte cultures. IL-1β exerts its effects via the transcription factor NF-κB, and suggesting mechanism, laquinimod pretreatment of human astrocytes downregulated NF-κB activation. Conclusions: Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act centrally on resident CNS cells to restrict pathology in MS lesions. Supported by: A research grant from Teva Pharmaceuticals. Disclosure: Dr. Pham has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Hayardeny Nisimov has nothing to disclose. Dr. John has received personal compensation for activities with EMD Serono, Teva Neuroscience, and Biogen Idec. Dr. John has received research support from Teva Neuroscience, and Vaccinex Inc.

Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-1009-1) contains supplementary material, which is available to authorized users.