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Barrier -protective function Barrier-protective function of of intestinal intestinal epithelial epithelial TLR2 TLR2 Elke Cario Division of Gastroenterology & Hepatology University Hospital of Essen Essen, Germany The The intestinal intestinal epithelial epithelial layer layer functions functions as as an an innate innate and and adaptive adaptive immune immune barrier barrier towards towards the the resident resident microflora microflora Science 2005 307:1920 Bacterial Bacterial lipoproteins lipoproteins activate activate TLR2 TLR2 signalling signalling resulting resulting in in NFκB NFκB activation activation and and cytokine cytokine production production in in IEC IEC IEC Am J Pathol 2002;160:165 TLR2 TLR2 stimulation stimulation induces induces ZO-1 ZO-1 redistribution redistribution via via PKC PKC which which correlates correlates with with TER TER increase increase Time (mins) in vitro 0 15 30 60 120 PMA 78-85 panPKC 78-80 ZO-1 + PCSK 20µg/ml TER (% of negative controls) Phospho- panPKC PCSK 20µg/ml 200 150 100 50 0 0 15 30 45 60 75 Time (mins) TLR2DN Gastroenterology 2004;127:224 TLR4DN 90 105 120 TLR2-induced TLR2-induced PI3K-Akt PI3K-Akt promotes promotes IEC IEC anti-apoptosis anti-apoptosis p<0.0001 Gastroenterology 2007 132:1359 TLR2 TLR2 protects protects intestinal intestinal epithelial epithelial TJ-associated TJ-associated barrier barrier assembly assembly via via PI3K-Akt PI3K-Akt + PCSK WT Ex-vivo MyD88-/- TLR2-/- WT - PCSK +PCSK LY249002 / +PCSK 3D-reconstruction, 45° Gastroenterology 2007 132:1359 Inflammatory Inflammatory stress stress in in mice mice deficient deficient of of TLR2 TLR2 or or MyD88 MyD88 induces induces early early TJ-associated TJ-associated barrier barrier disruption disruption TLR2-/- MyD88-/- DSS 4%, Day 5 ZO-1 H 2O Gastroenterology 2007 132:1359 WT DSS-colitis DSS-colitis also also disrupts disrupts E-cadherin E-cadherin in in TLR2-/TLR2-/- and and MyD88-/-, MyD88-/-, but but not not in in WT WT MyD88-/- WT TLR2-/- MyD88-/TLR2-/- TLR2-/- WT WT MyD88-/- E-cadherin H2O ZO-1 E-cadherin DSS 4%, Day 5 ß-actin H2O DSS 4% Day 5 Gastroenterology 2007 132:1359 Toxic Toxic stress-mediated stress-mediated TJ-associated TJ-associated barrier barrier disassembly disassembly results results in in deficient deficient anti-apoptotic anti-apoptotic IEC IEC protection protection Gastroenterology 2007 132:1359 p<0.001 p>0.05 Cytokeratin/PI/Tunel Surface IEC Treatment Treatment with with TLR2 TLR2 agonist agonist ameliorates ameliorates all all clinical clinical signs signs of of DSS-induced DSS-induced colonic colonic inflammation inflammation 6 % Body weight 90 # 5 * + 100 # * * 4 * - PCSK + PCSK 80 Stop DSS 70 12 Blood score Day 0 *p<0.001 110 PCSK 150µg/ml DSS 2.7% - PCSK + PCSK Stop DSS + *p<0.001 3 2 * 1 0 Day Gastroenterology 2007 132:1359 § § -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Day WT * # PCSK -1 0 1 2 3 4 5 6 7 8 9 10 11 12 PCSK The The TLR2 TLR2 ligand ligand PCSK PCSK attenuates attenuates severity severity of of DSS DSS colitis colitis Gastroenterology 2007 132:1359 DSS-mice DSS-mice treated treated with with TLR2 TLR2 agonist agonist demonstrate demonstrate lower lower FITC-dextran FITC-dextran serum serum levels levels 2500 Overlay FITC in situ + H&E Day 10 +DSS - PCSK [FITC] ng/ml 2000 + PCSK 1500 1000 § 500 C on tr ol -P C SK + PC SK 0 Gastroenterology 2007 132:1359 DSS 2.7%, Day 10 PCSK-treatment PCSK-treatment leads leads to to substantial substantial preservation preservation of of TJ/AJ TJ/AJ architecture architecture of of IEC IEC in in DSS DSS colitis colitis - PCSK + PCSK DSS 2.7%, Day 12 ZO-1 * * * E-cadherin * * * inflammatory infiltrate * Gastro 2007 132:1359 TLR2-mediated TLR2-mediated stabilization stabilization of of barrier barrier integrity integrity correlates correlates with with less less mucosal mucosal apoptosis apoptosis after after DSS DSS exposure exposure DSS 2.7%, Day 12 *p<0.05 Cytokeratin/PI/Tunel Gastroenterology 2007 132:1359 Human Human TLR2 TLR2 expression expression fails fails to to increase increase in in inflamed inflamed epithelium epithelium in in IBD IBD Healthy Active CD Inactive UC Active CD Infect Immun 2000;68:7010 TLR2 TLR2 modulates modulates the the functions functions of of CD4+/CD25+ CD4+/CD25+ regulatory regulatory TT cells cells in in SCID SCID colitis colitis PNAS 2006;103:7048 Oral Oral LcrV-secreting LcrV-secreting LL lactis lactis induces induces IL-10 IL-10 via via TLR2 TLR2 preventing preventing TNBS-colitis TNBS-colitis IL10 ↑ Gastroenterology 2007 133:862 via TLR2 Conclusion Conclusion Î TLR2 may provide a novel target to pharmacologically modulate acute mucosal barrier injury and intestinal inflammation.