Inflammatory Pathways in Sepsis: TLRs and Innate Immunity. Keith R. Walley, MD St. Paul s Hospital University of British Columbia Vancouver, Canada

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1 Inflammatory Pathways in Sepsis: TLRs and Innate Immunity Keith R. Walley, MD St. Paul s Hospital University of British Columbia Vancouver, Canada

2 Early Goal-Directed Therapy Rivers E et al. NEJM 345: , 2001

3 Early Resuscitation Limits the Innate Immune Response Why does early resuscitation work in any form of shock? Why does delayed resuscitation (any shock) result in distributive shock? Why does sterile severe pancreatitis look like septic shock? INJURY AND INFECTION SHARE THE SAME EARLY INFLAMMATORY PATHWAYS TLRs and Innate Immunity

4 PAMPs Pathogen-Associated Molecular Patterns DNA DNA viruses PGN Gram+, yeast LPS Gram- RNA RNA viruses Toll-Like Receptors (TLRs) on WBCs Wang et al. Microbes Infect (2009)

5 DAMPs Damage-Associated Molecular Patterns DNA (hepatocytes, cardiomyocytes) HSP60, HSP70 HSPs, S100A8 / A9 HMGB1 RNA (trophoblast) Endogenous TLR Ligands on many cells Wang et al. Microbes Infect (2009)

6 Cardiomyocytes express Toll-like receptors Boyd et al. Cardiovascular Research. 72: , 2006

7 TLR ligands decrease contractility TLR2 TLR4 TLR5 Boyd et al. Cardiovascular Research. 72: , 2006

8 NF- B Activity DAMPs that increase NF- B in heart cells Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Circ J. 75: , 2011

9 HSP70 increases inflammation and decreases contractility Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Circ J. 75: , 2011

10 HSP70 decreases contractility via TLR2 HSP70 10 g/ml HSP70 10 g/ml Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Circ J. 75: , 2011

11 S100A8 and S100A9 are expressed during myocardial inflammation Induced by TLRs Boyd et al. Circ Res. 102: , 2008

12 Contractility S100A8 and S100A9 contractility Boyd et al. Circ Res. 102: , 2008

13 Any evidence that TLRs make a difference in human sepsis?

14 Innate immune genetic variants alter susceptibility to the corresponding infection Gram- LPS / CD14 Mannose Binding Lectin (MBL) binds all pathogen carbohydrate Gram + and Gram - Gram + Gram - Sutherland AM, Walley KR, Russell JA. Critical Care Medicine. 33(3):638-44, 2005

15 Gram+ TLR1 genetic variant alters culture positivity and survival Wurfel MM et al. Am J Respir Crit Care Med. 178:710-20, 2008

16 IRAK-4 genetic variant alters culture positivity Sutherland AM et al. J Innate Immun, 3(5):447-58, 2011.

17 Is there anything we can do? Early treatment of infection (PAMPs) reduce pathogen load clear endotoxins faster Why does early resuscitation work in any form of shock? reduce DAMP release (e.g. HSP70)

18 Co-investigator John Boyd Funding Heart & Stroke Foundation CIHR Michael Smith Foundation People Yingjin Wang Ryon Bateman Chiho Tokunaga Edmond Chau Ehsan Davani Haley Roberts Thoma Kareco Sumeet Mathur Sorel Bosan

19 EXTRA SLIDES

20 S100A8 / S100A9 Bind TLR4 Ehrchen JM et al. J. Leukoc. Biol. 86: ; 2009

21 DAMPs Damage-Associated Molecular Patterns DNA (hepatocytes, cardiomyocytes) HSP60, HSP70 HSPs, S100A8 / A9 RNA (trophoblast) Endogenous TLR Ligands on many cells Wang et al. Microbes Infect (2009)

22 CpG binds TLR9 and induces counter-regulatory A20 (TNFAIP3) Murine Myocardial Ischemia-Reperfusion Mathur S, Walley KR, Boyd JH. Shock. 36(5): , 2011.

23 Early Resuscitation Limits the Innate Immune Response Why does early resuscitation work in any form of shock? Why does delayed resuscitation (any shock) result in distributive shock? Why does sterile severe pancreatitis look like septic shock? INJURY AND INFECTION SHARE THE SAME EARLY INFLAMMATORY PATHWAYS TLRs and Innate Immunity

24 ICAM-1 expression on activated cardiomyocytes * A B

25 ICAM-1 binding signals through the cytoskeleton (FAK) Control ICAM-1 Cross-linked Davani et al. Am J Physiol Heart Circ Physiol. 287(3):H , 2004.

26 Decreased contractility is due to heterogeneous Ca 2+ release Davani et al. Am J Physiol Heart Circ Physiol. 287(3):H , 2004.

27 What binds ICAM-1? Fibrinogen (brown) extravasates into myocardium during inflammation Control Endotoxin

28 Decreased Contractility: Fibrinogen binding ICAM-1 Untreated Albumin Fibrinogen Denatured Fibrinogen

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30 S100A8 and S100A9 contractility by binding RAGE (maybe SERCA2) RAGE: Receptor for Advanced Glycation End products - Also binds TLR4 Boyd et al. Circ Res. 102: , 2008

31 TLR ligands signal via NF- B to induce cytokine production by cardiomyocytes Con TLR Ligand Boyd et al. Cardiovascular Research. 72: , 2006.

32 TLR-mediated ICAM-1 expression is NF B-dependent (PDTC inhibits) TLR2 TLR4 TLR5 Boyd et al. Cardiovascular Research. 72: , 2006.

33 NIK