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Molecular signalling in inflammation 2 lectures 2 nd Med Molecular Medicine

Molecular signalling in inflammation 2 lectures 2 nd Med Molecular Medicine. Andrew Bowie, School of Biochemistry and Immunology. Definition of Inflammation.

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Molecular signalling in inflammation 2 lectures 2 nd Med Molecular Medicine

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  1. Molecular signalling in inflammation2 lectures2nd Med Molecular Medicine Andrew Bowie, School of Biochemistry and Immunology

  2. 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

  3. The molecular basis? • The key stages: • Initiation… • Signal transduction… • Altered gene expression… • Resolution

  4. Initiation of inflammation • Infection-induced inflammation now well characterised • ‘Sterile Inflammation’ is not • Rheumatoid Arthritis • Atherosclerosis • IBD • Psoriasis

  5. 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)

  6. TLRs are PRRs for PAMPs Medzhitov (2001) Nature Rev. Immunol. 1, 135

  7. 2. Toll-Like 1. IL-1RI-Like Insects dToll 1-8 hTLR1 hTLR2 hTLR3 hTLR4 hTLR5 hTLR6 hTLR7 hTLR8 hTLR9 hTLR10 mTLR11 mTLR12 mTLR13 IL-1RI 1L-1RAcP IL-18R IL-18RAcP IL-1Rrp2 T1/ST2 IL-1RAPL TIGIRR-1 Mammals Mammals SIGIRR N L6 RPPs Plants 3. TIR Adaptors MyD88, Mal, TRIF, TRAM SARM

  8. TLRs have a role in both the innate and adaptive immune responses NO TNF, IL-6 Adapted from Medzhitov (2001) Nature Rev. Immunol. 1, 135

  9. NODs • Implicated in inflammatory diseases • Intracellular proteins • Some are PRRs • NOD domain • LRR domain • Effector domains (e.g. CARD)

  10. RLRs (and TLRs) recognise viral RNA Taken from Akira et al., Cell 124, 783-801, 2006

  11. 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’

  12. Detection of PAMPs and DAMPs by TLRs Karin et al., (2006) Cell 124, 823

  13. Overview of gene induction • Signalling pathways affect gene induction • DNA  mRNA  Protein • Transcription • Regulation of RNA (stabilisation, splicing) • Translation • Post-translational modification

  14. 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. NFkB) • MAP kinases activated (e.g. p38 MAPK) • The inflammasome & caspases activated

  15. NFkB Activator P Degradation ? P IkBa p50 p65 IkBa Gene Induction p65 p50 • Central mediator of immune and inflammatory responses. • Activated by diverse stimuli. • Role in many physiological and pathological processes.

  16. Phosphorylation of IKKs Cyto IKK complex g a b Nuc P P IkBa p50 p65 IkBa p65 p65 p50 p50 Ubiquitination by E3 Ligase Gene Indn Degradation

  17. PKA NIK PI3K RIP MEKK1 PKCz Phosphorylation of IKKs S6 KINASE Cyto IKK complex MEKK 2 + 3 g a b Nuc P P IkBa p50 p65 IkBa p65 p65 p50 p50 Ubiquitination by E3 Ligase Gene Indn Degradation IRAK? TAK1 TPL-2 p105 Phosp and degrad Y42Phosp p65Phosp

  18. TLR MyD88 IRAK TRAF6 IKK NFkB Basic signalling paradigm for TLRs leading to NFkB activation

  19. LPS TRAM Mal TIR IRAK2 TIR TIR MyD88 IRAK4 TRIF IRAK1 TIR TIR TIR TRAF6 DD RIP1 TAB2/3 Uq TAK1 How LPS (via TLR4) causes NFkB activation NEMO IKKa IKKb P P I-kB NF-kB P NF-kB nucleus

  20. IRAKs IRAKs IRAKs IRAKs TRAF6 TRAF6 TRAF6 TRAF6 TLR2/1 or 2/6 TLR3 TLR4 TLR5 TLR7/8/9 MD2 MyD88 TRIF Mal MyD88 TRIF MyD88 MyD88 Mal TRAM RIP1 TBK1 TBK1 NFkB NFkB IRF3 IRF5/7 NFkB IRF3 NFkB NFkB IFNa TNFa IL6 IL8 TNFa IL6 IL8 TNFa IFNb IL6 RANTES IL8 TNFa IFNb IL6 RANTES IL8 TNFa IL6 IL8

  21. 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

  22. Caspase 1

  23. Caspase 1 is activated by the inflammasome …but what activates the inflammasome??

  24. How NODs signal changes in gene expression

  25. Aberrant NOD signalling in disease

  26. 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)

  27. TNF • Proinflammatory and apoptotic • Key role in RA • How it signals • How its regulated

  28. Regulation of TNF production and function • TNF gene expression – NFkB and p38 • Membrane bound initially (cleaved by TACE) • Receptor shedding • Receptor endocytosis • SODD (silencer of death domains) • TRIP (TRAF interacting protein), A20. • NFkB/IkB autoregulation

  29. Normally, initiation of inflammation (e.g. by TLR4) is tightly regulated

  30. 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.

  31. Reading list • Akira & Takeda (2004) Toll-like receptor signalling. Nature Reviews Immunology4: 499-511 • Inohara & Nunez (2003) NODs: Intracellular proteins involved in inflammation and apoptosis. Nature Reviews Immunology3: 371-382 • Meylan, Tschopp & Karin (2006) Intracellular pattern recognition receptors in the host response. Nature442: 39-44 • Kanneganti, Lamkanfi & Nunez (2007) Intracellular NOD-like Receptors in Host Defense and Disease. Immunity27: 549-559

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