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Molecular signalling in inflammation 2 lectures 2 nd Med Molecular Medicine Andrew Bowie, School of Biochemistry and Immunology
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Definition of Inflammation A normally beneficial host response to foreign challenge or tissue injury that leads ultimately to the restoration of tissue structure and function. Normally is self-limiting while prolonged inflammation can lead to disease
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The molecular basis? The key stages: Initiation… Signal transduction… Altered gene expression… Resolution
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Initiation of inflammation 1.Infection-induced inflammation now well characterised 2.‘Sterile Inflammation’ is not 1. Rheumatoid Arthritis 2.Atherosclerosis 3.IBD 4.Psoriasis
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Initiation of inflammation by infection Quasi-infectious stimuli (e.g. LPS) used for decades to model inflammation and sepsis Inflammatory mediators involved, and their effects well- characterised Only recently have the initiating events been described. Involves PRRs recognising PAMPs Three key families of PRRs: –Toll-like receptors (TLRs) –Nucleotide-binding oligomerisation domain proteins (NODs) –RIG-I-like receptors (RLRs)
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TLRs are PRRs for PAMPs Medzhitov (2001) Nature Rev. Immunol. 1, 135
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2. Toll-Like 1. IL-1RI-Like dToll 1-8 hTLR1 hTLR2 hTLR3 hTLR4 hTLR5 hTLR6 hTLR7 hTLR8 hTLR9 hTLR10 mTLR11 mTLR12 mTLR13 N L6 RPPs IL-1RI 1L-1RAcP IL-18R IL-18RAcP IL-1Rrp2 T1/ST2 IL-1RAPL TIGIRR-1 SIGIRR Mammals Plants Insects 3. TIR Adaptors MyD88, Mal, TRIF, TRAM SARM
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TLRs have a role in both the innate and adaptive immune responses Adapted from Medzhitov (2001) Nature Rev. Immunol. 1, 135 NO TNF, IL-6
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NODs Implicated in inflammatory diseases Intracellular proteins Some are PRRs NOD domain LRR domain Effector domains (e.g. CARD)
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Taken from Akira et al., Cell 124, 783-801, 2006 RLRs (and TLRs) recognise viral RNA
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Sterile inflammation Vs infection-induced Little known about sterile inflammation but probably involves many of the same pathways Similar end-points, e.g. TNF production Therapeutic opportunity: upsteam blockade of signalling rather than targetting individual downstream cytokines Endogenous ligands of TLRs initiate it? ‘Danger signals’
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Detection of PAMPs and DAMPs by TLRs Karin et al., (2006) Cell 124, 823
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Overview of gene induction Signalling pathways affect gene induction DNA mRNA Protein Transcription Regulation of RNA (stabilisation, splicing) Translation Post-translational modification
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Signalling by TLRs, NODs &RLS Leads to changes in gene induction These genes encode many inflammatory mediators (N.B. IL-1 and TNF) Transcription factors activated (e.g. NF B) MAP kinases activated (e.g. p38 MAPK) The inflammasome & caspases activated
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NF B Central mediator of immune and inflammatory responses. Activated by diverse stimuli. Role in many physiological and pathological processes. IBIB p50 p65 Activator p65 p50 P IBIB P Degradation Gene Induction ?
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P P IBIB IBIB p65 p50 p65 IKK complex Ubiquitination by E3 Ligase Degradation p65 p50 Gene Indn Phosphorylation of IKKs Cyto Nuc
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P P IBIB IBIB p65 p50 p65 IKK complex Ubiquitination by E3 Ligase Degradation p65 p50 Gene Indn Phosphorylation of IKKs Cyto Nuc PKC NIK TAK1 MEKK1 S6 KINASE MEKK 2 + 3 TPL-2 p105 Phosp and degrad p65 Phosp PKA Y42 Phosp PI3KRIP IRAK?
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Basic signalling paradigm for TLRs leading to NF B activation TLR MyD88 IRAK TRAF6 IKK NF B
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nucleus TRIF TIR NEMO IKK IKK TAB2/3 TAK1 RIP1 TRAF6 Uq NF- BI- B P P NF- B P TIR LPS TIR TRAM DD TIR Mal MyD88 IRAK4 IRAK1 IRAK2 How LPS (via TLR4) causes NF B activation
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MyD88 TRIF Mal MyD88 TRIF MyD88 MyD88 MD2 TLR2/1 or 2/6 TLR3 TLR4 TLR5 TLR7/8/9 Mal NF B NF B IRF3 NF B TNF IL6 IL8 TNF IFN IL6 RANTES IL8 TNF IFN IL6 RANTES IL8 TNF IL6 IL8 IRAKs TRAF6 RIP1 TBK1 IRAKs TRAF6 IRAKs TRAF6 IRAKs TRAF6 NF B TNF IL6 IL8 IRF5/7 IFN TRAM
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P38 MAP kinase Activated by TLR pathways TRAF6 TAK1 MKK MAP kinase P38 phosphorylates some Txn Factors P38 has a role in stabilising cytokine mRNA
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Caspase 1
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Caspase 1 is activated by the inflammasome …but what activates the inflammasome??
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How NODs signal changes in gene expression
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Aberrant NOD signalling in disease
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IL-1 Gene upregulated in inflammation Pro-IL-1 cleaved by ICE (Caspase 1) Secreted IL1R1, IL-1R2, IL1ra IL-1 signalling cascade Gene induction (IL-8, CAMs, COX, iNOS)
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TNF Proinflammatory and apoptotic Key role in RA How it signals How its regulated
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Regulation of TNF production and function TNF gene expression – NF B and p38 Membrane bound initially (cleaved by TACE) Receptor shedding Receptor endocytosis SODD (silencer of death domains) TRIP (TRAF interacting protein), A20. NF B/I B autoregulation
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Normally, initiation of inflammation (e.g. by TLR4) is tightly regulated
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Resolution of inflammation Further gene products and lipid mediators Suppress pro-inflammatory gene expression Inhibit cell trafficking Induce apoptosis of inflammatory cells Injurious stimulus cleared Normal tissue structure and function restored.
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Reading list 1.Akira & Takeda (2004) Toll-like receptor signalling. Nature Reviews Immunology 4: 499-511 2.Inohara & Nunez (2003) NODs: Intracellular proteins involved in inflammation and apoptosis. Nature Reviews Immunology 3: 371-382 3.Meylan, Tschopp & Karin (2006) Intracellular pattern recognition receptors in the host response. Nature 442: 39-44 4.Kanneganti, Lamkanfi & Nunez (2007) Intracellular NOD-like Receptors in Host Defense and Disease. Immunity 27: 549-559
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