Innate immunity as a therapeutic target in IBD Elke Cario Division of Gastroenterology & Hepatology University Hospital of Essen Essen, Germany
The intestinal mucosa must rapidly recognize luminal pathogens to initiate controlled immune responses, but maintain hyporesponsiveness to harmless commensals Science 2005 307:1920
The Principle of Pattern Recognition Innate immune cells express so-called pattern recognition receptors (PRRs( PRRs),, that specifically discriminate between self and microbial non-self, based on the recognition of broadly conserved molecular patterns. Janeway PRR pro/anti anti-inflammatoryinflammatory antimicrobial Adaptive Immunity
Families of PRRs: TLRs, NLRs, cell surface TREM CD11 CD18 Toll-like like receptors MD-2 mcd14 (TLRs) soluble LBP scd14...and many more Nods/CARDs intracellular
TLR-KO mice are susceptible to acute DSS colitis Mechanism Colitis - Model Activity Knockout WT MyD88-/- TLR2-/- Toxic damage (target: IEC) DSS - acute TLR2-/- TLR4-/- TLR9-/- MyD88-/- Gastro 2007 132:1359 % Survival 100 75 50 WT TLR2-/- MyD88-/- 25 Stop DSS 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Day Epithelial injury Cell 2004;118:229
Some TLR5KO develop spontaneous colitis which is TLR4-dependent J Clin Invest 2007 117: 3909 TLR4/5KO
Treatment with TLR2 agonist ameliorates all clinical signs of DSS-induced colonic inflammation Day DSS 2.7% PCSK 150µg/ml 0 6 12 % Body weight 110 100 90 80 70 - PCSK + PCSK Stop DSS * * * PCSK * # -1 0 1 2 3 4 5 6 7 8 9 10 11 12 + Day *p<0.001 # Blood score 5 4 3 2 1 0 - PCSK + PCSK Stop DSS -1 0 1 2 3 4 5 6 7 8 9 10 11 12 + Day * PCSK * *p<0.001 # Gastroenterology 2007 132:1359 WT
The TLR2 ligand PCSK attenuates severity of DSS colitis Gastroenterology 2007 132:1359
TLR2 stimulation induces ZO-1 redistribution via PKC which correlates with TER increase Time (mins( mins) 0 15 30 60 120 Phospho- panpkc 78-85 85 panpkc PMA 78-80 80 PCSK 20µg/ml in vitro ZO-1 + PCSK 20µg/ml TER (% of negative controls) 200 150 100 50 0 0 15 30 45 60 75 90 105 120 Time (mins) TLR2DN TLR4DN Gastroenterology 2004;127:224
PCSK-treatment leads to substantial preservation of TJ/AJ architecture of IEC in in DSS colitis -PCSK + PCSK * DSS 2.7%, Day 12 ZO-1 * * * E-cadherin * * * inflammatory infiltrate Gastro 2007 132:1359
DSS-mice treated with TLR2 agonist demonstrate lower FITC-dextran serum levels 2500 2000 Day 10 +DSS -PCSK Overlay FITC in situ + H&E + PCSK [FITC] ng/ml 1500 1000 500 0 Control - PCSK + PCSK Gastroenterology 2007 132:1359 DSS 2.7%, Day 10
Epithelial cell TLR engagement stimulates extension and antigen sampling of underlying dendritic cells TLR TLR J Immunol 2006 176:4275 JEM 2006 203:2841 Immunity 2006 24:623 Science 2005 307:254 Nat Immunol 2001 2:361
TLR inhibition protects against TH1-mediated colitis Mechanism Toxic damage (IEC, T cell etc.) T-cell-mediated Cell Res 2006;16:70 TNBS IL-12 IL-18 Aktivity wt TLR9-/- TLR9-/- Knockout TLR4-/- TLR4-/- Colitis - Model DSS chronic TNBS x Stat3mutant x IL10-/- MyD88-/- Chron. DSS TNFα IL-6 IFNγ Gastroenterology 2005;129:913
TLR4/MyD88 trigger chronic intestinal inflammation through aberrant myeloid cell activation in in the absence of of IL-10 JCI 2003 111:1297 MyD88/IL-10-/- TLR4/Stat3-/- IL-10 10-/- TLR-/- Immunity 2006 25:1 = TH1
TLR4 blockage with CRX-526 ameliorates spontaenous colitis in MDR1α-deficient mice MDR1α-deficient mice Severe colitis No colitis + CRX-526 synthetic lipid A mimetic TLR4 antagonist + vehicle J Immunol 2005 174:6416
TLR signalling may not be involved in all forms of chronic murine colitis Mechanism T-cell-mediated Colitis - Model x IL2-/- CD4 + CD62L + T cell transfer Aktivity Knockout TLR9-/- MyD88-/- MyD88/IL2-/- itreg IL-27 STOP Th17 Immunity 2006;25:1 Eur J Immunol 2007;37:1809
Two autophagy-genes ATG16L1 and IRGM have been associated with CD ATG16L1 Nat Genet. 2007 39:207 Nat Genet. 2007 39:596 Nat Genet. 2007; 39:830
MyD88-dependent signalling pathways contribute to intestinal tumor progression Science 2007;317:124
NOD2-overexpression protects against peptidoglycan- and TNBS-colitis PGN Colitis WT NOD2-Tg TNBS WT +/- NOD2 plasmid TNBS J Clin Invest 2008 118:545 Gastroenterology 2007 133:1510 +NOD2 +empty +mutnod2
Basal innate immune signaling may be protective of the IEC barrier against acute injury Acute injury intestinal epithelial barrier Commensals PRR Healing Barrier protection Tolerance Epithelium Gut. 2005 Aug;54(8):1182-93
Aberrant innate immune signaling may favor chronic intestinal inflammation through commensal-mediated mediated proinflammatory TH1-effects in the lamina propria Commensals PRR Invasion Cytokines Mucosa TH1-type Chronic inflammatory disease Gut. 2005 Aug;54(8):1182-93 Injury Barrier destruction Intolerance