Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11-mediated protection of regulatory T cells.

Abstract:

:Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing-remitting and chronic disease. Aspirin reduced the development of EAE driven by myelin basic protein (MBP)-specific T cells and the associated perivascular cuffing, inflammation, and demyelination. The effects of aspirin required the presence of CD25+FoxP3+ Tregs Aspirin increased the amounts of Foxp3 and interleukin-4 (IL-4) in T cells and suppressed the differentiation of naïve T cells into T helper 17 (TH17) and TH1 cells. Aspirin also increased the transcription of Il11 mediated by the transcription factor CREB, which was necessary for the generation of Tregs Neutralization of IL-11 negated the effects of aspirin on Treg development and exacerbated EAE. Furthermore, we found that IL-11 alone was sufficient to maintain the percentage of FoxP3+ Tregs and protect mice from EAE. These results identify a previously uncharacterized mode of action of aspirin.

journal_name

Sci Signal

journal_title

Science signaling

authors

Mondal S,Jana M,Dasarathi S,Roy A,Pahan K

doi

10.1126/scisignal.aar8278

subject

Has Abstract

pub_date

2018-11-27 00:00:00

issue

558

eissn

1945-0877

issn

1937-9145

pii

11/558/eaar8278

journal_volume

11

pub_type

杂志文章
  • Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation.

    abstract::Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that indiv...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf3998

    authors: Bagnall J,Boddington C,England H,Brignall R,Downton P,Alsoufi Z,Boyd J,Rowe W,Bennett A,Walker C,Adamson A,Patel NMX,O'Cualain R,Schmidt L,Spiller DG,Jackson DA,Müller W,Muldoon M,White MRH,Paszek P

    更新日期:2018-07-24 00:00:00

  • Sorting out memory and learning.

    abstract::Mutations in AMPA receptor recycling machinery underlie cognitive impairment in an intellectual disorder and in neurodegenerative diseases. ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aan5454

    authors: Ferrarelli LK

    更新日期:2017-05-02 00:00:00

  • Full focus on calcium.

    abstract::Intracellular calcium (Ca2+) signals are of prime importance for cellular function and behavior and are underpinned by a plethora of Ca2+ channels, pumps, transporters, and binding proteins that are regulated in complex ways. A series of biennial meetings, the International Meetings of the European Calcium Society (EC...

    journal_title:Science signaling

    pub_type:

    doi:10.1126/scisignal.aaz0961

    authors: Parys JB,Guse AH

    更新日期:2019-09-17 00:00:00

  • mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1-induced collagen biosynthesis.

    abstract::The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue r...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aav3048

    authors: Selvarajah B,Azuelos I,Platé M,Guillotin D,Forty EJ,Contento G,Woodcock HV,Redding M,Taylor A,Brunori G,Durrenberger PF,Ronzoni R,Blanchard AD,Mercer PF,Anastasiou D,Chambers RC

    更新日期:2019-05-21 00:00:00

  • Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis.

    abstract::Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and canc...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aao5150

    authors: Yang Y,Li S,Jin ZR,Jing HB,Zhao HY,Liu BH,Liang YJ,Liu LY,Cai J,Wan Y,Xing GG

    更新日期:2018-10-16 00:00:00

  • De novo organ formation from differentiated cells: root nodule organogenesis.

    abstract::The symbiotic interaction between Rhizobium bacteria and legume plants leads to the induction of a new developmental program: the formation of nitrogen-fixing root nodules. Nodulation is triggered by specific bacterial signals, the Nod factors, and integrates plant developmental regulatory pathways to reactivate diffe...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.149re11

    authors: Crespi M,Frugier F

    更新日期:2008-12-09 00:00:00

  • A large bioactive BMP ligand with distinct signaling properties is produced by alternative proconvertase processing.

    abstract::Dimers of conventional transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) ligands are composed of two 100- to 140-amino acid peptides that are produced through the proteolytic processing of a proprotein precursor by proconvertases, such as furin. We report the identification of an evolutionarily...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002549

    authors: Akiyama T,Marqués G,Wharton KA

    更新日期:2012-04-03 00:00:00

  • Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function.

    abstract::Chimeric antigen receptors (CARs) link an antigen recognition domain to intracellular signaling domains to redirect T cell specificity and function. T cells expressing CARs with CD28/CD3ζ or 4-1BB/CD3ζ signaling domains are effective at treating refractory B cell malignancies but exhibit differences in effector functi...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aat6753

    authors: Salter AI,Ivey RG,Kennedy JJ,Voillet V,Rajan A,Alderman EJ,Voytovich UJ,Lin C,Sommermeyer D,Liu L,Whiteaker JR,Gottardo R,Paulovich AG,Riddell SR

    更新日期:2018-08-21 00:00:00

  • Arabidopsis jasmonate signaling pathway.

    abstract::Jasmonates control defense gene expression, growth, and fertility throughout the plant kingdom and have been studied extensively in Arabidopsis thaliana. The prohormone jasmonic acid (JA) is conjugated to amino acids such as isoleucine to form the active hormone jasmonoyl-isoleucine (JA-Ile). A series of breakthroughs...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.3109cm4

    authors: Gfeller A,Liechti R,Farmer EE

    更新日期:2010-02-16 00:00:00

  • Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway.

    abstract::Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3-mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. Afte...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal4064

    authors: Liu X,Gong B,de Souza LB,Ong HL,Subedi KP,Cheng KT,Swaim W,Zheng C,Mori Y,Ambudkar IS

    更新日期:2017-06-06 00:00:00

  • TGF-β-mediated enhancement of TH17 cell generation is inhibited by bone morphogenetic protein receptor 1α signaling.

    abstract::The cytokines of the transforming growth factor-β (TGF-β) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-β, in regulating the immune responses has been extensively studied. TGF-β is critical to prevent the spontaneous activation of self-reactive T cells...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aar2125

    authors: Browning LM,Pietrzak M,Kuczma M,Simms CP,Kurczewska A,Refugia JM,Lowery DJ,Rempala G,Gutkin D,Ignatowicz L,Muranski P,Kraj P

    更新日期:2018-08-28 00:00:00

  • Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease.

    abstract::Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf6209

    authors: Alfonso SI,Callender JA,Hooli B,Antal CE,Mullin K,Sherman MA,Lesné SE,Leitges M,Newton AC,Tanzi RE,Malinow R

    更新日期:2016-05-10 00:00:00

  • Dynamic DNA methylation regulates neuronal intrinsic membrane excitability.

    abstract::Epigenetic modifications, such as DNA cytosine methylation, contribute to the mechanisms underlying learning and memory by coordinating adaptive gene expression and neuronal plasticity. Transcription-dependent plasticity regulated by DNA methylation includes synaptic plasticity and homeostatic synaptic scaling. Memory...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf5642

    authors: Meadows JP,Guzman-Karlsson MC,Phillips S,Brown JA,Strange SK,Sweatt JD,Hablitz JJ

    更新日期:2016-08-23 00:00:00

  • Regulation of type I interferon: It's HIP to be K2.

    abstract::Uncontrolled expression of type I interferon (IFN-I) drives autoimmunity, necessitating the need for tight regulation. In this issue, Cao et al reveal a role for the kinase HIPK2 in the transcriptional control of IFN-I during antiviral immune responses. ...

    journal_title:Science signaling

    pub_type: 评论,杂志文章,评审

    doi:10.1126/scisignal.aaw8549

    authors: Best SM,Ponia SS

    更新日期:2019-03-19 00:00:00

  • Using functional signature ontology (FUSION) to identify mechanisms of action for natural products.

    abstract::A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004657

    authors: Potts MB,Kim HS,Fisher KW,Hu Y,Carrasco YP,Bulut GB,Ou YH,Herrera-Herrera ML,Cubillos F,Mendiratta S,Xiao G,Hofree M,Ideker T,Xie Y,Huang LJ,Lewis RE,MacMillan JB,White MA

    更新日期:2013-10-15 00:00:00

  • The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils.

    abstract::Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain-like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NA...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aao1716

    authors: D'Cruz AA,Speir M,Bliss-Moreau M,Dietrich S,Wang S,Chen AA,Gavillet M,Al-Obeidi A,Lawlor KE,Vince JE,Kelliher MA,Hakem R,Pasparakis M,Williams DA,Ericsson M,Croker BA

    更新日期:2018-09-04 00:00:00

  • Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation.

    abstract::The role of the mitochondrial Ca2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output),...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aav1439

    authors: Koval OM,Nguyen EK,Santhana V,Fidler TP,Sebag SC,Rasmussen TP,Mittauer DJ,Strack S,Goswami PC,Abel ED,Grumbach IM

    更新日期:2019-04-30 00:00:00

  • Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors.

    abstract::Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs enco...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaw9252

    authors: Kennedy PR,Barthen C,Williamson DJ,Pitkeathly WTE,Hazime KS,Cumming J,Stacey KB,Hilton HG,Carrington M,Parham P,Davis DM

    更新日期:2019-12-17 00:00:00

  • Drosophila toll pathway: the new model.

    abstract::In Drosophila, recognition of microbe-specific molecules (such as bacterial peptidoglycans) activates serine protease cascades that converge to activate the Toll pathway. Recent data show that the serine protease Grass, which is activated downstream of pattern recognition receptors and was initially thought to be a co...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.252jc1

    authors: Ashok Y

    更新日期:2009-01-06 00:00:00

  • Quantifying crosstalk among interferon-γ, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model.

    abstract::T helper (T(H)) cells integrate biochemical cues present in the tissue microenvironment and produce cytokines that orchestrate immune responses. Previous discoveries have revealed a qualitative understanding of how T(H) cells process this biochemical information; however, the lack of methods to quantify how well these...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002657

    authors: Klinke DJ 2nd,Cheng N,Chambers E

    更新日期:2012-04-17 00:00:00

  • Cracking the NF-κB code.

    abstract::The discovery of feedback loops between signaling and gene expression is ushering in new quantitative models of cellular regulation. In a recent issue of Science Signaling, Sung et al. showed how positive feedback downstream of nuclear factor κB (NF-κB) signaling enhances the capacity of macrophages to scale their ant...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.2005108

    authors: Tkach KE,Oyler JE,Altan-Bonnet G

    更新日期:2014-02-18 00:00:00

  • TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α.

    abstract::Transforming growth factor-β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal4186

    authors: Hamidi A,Song J,Thakur N,Itoh S,Marcusson A,Bergh A,Heldin CH,Landström M

    更新日期:2017-07-04 00:00:00

  • Dissecting the signaling pathways that mediate cancer in PTEN and LKB1 double-knockout mice.

    abstract::Double knockout of PTEN and LKB1-genes encoding phosphatase and tensin homolog and liver kinase B1, respectively-leads to the spontaneous development of cancer in mice. PTEN converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2), whereas LKB1 activates the 5' adeno...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.aac8321

    authors: Chen J,Zhang XD,Proud C

    更新日期:2015-09-01 00:00:00

  • A Wnt-fall for gene regulation: repression.

    abstract::A major endpoint of the canonical Wnt signaling pathway is a change in the transcription of target genes. The transcription factors lymphoid enhancer factor (LEF) and T cell factor (TCF) serve as the main gatekeepers of these changes by selecting genes to be targeted by the transcriptional coregulator beta-catenin and...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.139pe43

    authors: Hoverter NP,Waterman ML

    更新日期:2008-09-30 00:00:00

  • Acetylation of Ets-1 is the key to chromatin remodeling for miR-192 expression.

    abstract::By regulating gene expression, microRNAs (miRNAs) play pivotal roles in physiological and pathological processes. However, the regulation of miRNAs is elusive. miR-192 is a key regulator of renal fibrosis and hypertrophy in diabetic nephropathy. Natarajan et al. showed that the miR-192 gene contains an upstream region...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004299

    authors: Dong Z

    更新日期:2013-06-04 00:00:00

  • Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells.

    abstract::Cytotoxic lymphocytes share the presence of the activating receptor NK receptor group 2, member D (NKG2D) and the signaling-competent adaptor DNAX-activating protein 10 (DAP10), which together play an important role in antitumor immune surveillance. Ligand stimulation induces the internalization of NKG2D-DAP10 complex...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aab2724

    authors: Quatrini L,Molfetta R,Zitti B,Peruzzi G,Fionda C,Capuano C,Galandrini R,Cippitelli M,Santoni A,Paolini R

    更新日期:2015-10-27 00:00:00

  • Transglutaminase-catalyzed protein-protein cross-linking suppresses the activity of the NF-κB-like transcription factor relish.

    abstract::Cross-linking of proteins by mammalian transglutaminases (TGs) plays important roles in physiological phenomena such as blood coagulation and skin formation. We show that Drosophila TG suppressed innate immune signaling in the gut. RNA interference (RNAi) directed against TG reduced the life span of flies reared under...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2003970

    authors: Shibata T,Sekihara S,Fujikawa T,Miyaji R,Maki K,Ishihara T,Koshiba T,Kawabata S

    更新日期:2013-07-23 00:00:00

  • RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.

    abstract::Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2005301

    authors: Winter PS,Sarosiek KA,Lin KH,Meggendorfer M,Schnittger S,Letai A,Wood KC

    更新日期:2014-12-23 00:00:00

  • Focus issue: From genomic mutations to oncogenic pathways.

    abstract::This two-issue series focuses on how understanding how signaling pathways are altered in cancer cells can enable researchers to develop more effective therapies. Cancer is a pleiotropic disease. Tumor cells change over time and, even within a specific tumor, cells may have different mutations and dependencies on diffe...

    journal_title:Science signaling

    pub_type: 社论

    doi:10.1126/scisignal.2004149

    authors: Gough NR

    更新日期:2013-03-26 00:00:00

  • Network-level effects of kinase inhibitors modulate TNF-α-induced apoptosis in the intestinal epithelium.

    abstract::Individual signaling pathways operate in the context of the broader signaling network. Thus, the response of a cell to signals from the environment is affected by the state of the signaling network, such as the clinically relevant example of whether some components in the network are inhibited. The cytokine tumor necr...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aac7235

    authors: Gierut JJ,Wood LB,Lau KS,Lin YJ,Genetti C,Samatar AA,Lauffenburger DA,Haigis KM

    更新日期:2015-12-15 00:00:00