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The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases

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The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases REVIEW ARTICLE The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases Laszlo Romics, Jr, MD, PhD, MRCS; Gyongyi Szabo, MD, PhD; John Calvin Coffey, PhD, AFRCSI; Jiang Huai Wang, PhD; Henry Paul Redmond, MCh, FRCSI Objective: To outline the emerging significance of Toll- of pathogens renders them a key figure in the activation like receptor (TLR) signaling pathways in surgical dis- of both innate and adaptive immune responses during eases. sepsis. However, emerging evidence points to fundamen- tally important roles in ulcerative colitis, Crohn dis- Data Sources: A systematic review of the literature was ease, and Helicobacter pylori infection in the gastrointes- undertaken by searching the MEDLINE database for the tinal tract and in the development of atherosclerotic period 1966 to 2005 without language restriction. plaques in the cardiovascular system. Furthermore, re- cent studies suggest that the regulation of the TLR path- Study Selection: Original or review articles that de- way fulfills a central role in anticancer immunotherapy scribed experimental data on the activation of TLR sig- and in organ rejection after transplantation. naling pathways in surgically relevant diseases were se- lected for inclusion in this review. Conclusion: Given the clinical significance of TLR path- ways, the targeting of individual molecular components Data Extraction: Data were obtained from peer- is likely to offer a broad range of future therapeutic mo- reviewed articles and references. dalities. Data Synthesis: The role of TLRs in the recognition Arch Surg. 2006;141:595-601 OLL-LIKE RECEPTORS (TLRS) TLR5 is responsible for bacterial flagellin belong to the pattern rec- recognition. TLR9 is important in the rec- ognition receptor super- ognition of unmethylated CpG DNA de- family that recognizes dis- rived from bacteria. TLR1, TLR6, and tinct pathogen-associated TLR10 can coassociate with TLR2 and sub- Tmolecular patterns. They have a broad sequently enhance ligand specificity. range of functions, from being respon- Toll-like receptors represent an impor- sible for dorsoventral polarity in the Dro- tant link between the “innate” and “adap- sophila embryo1 to protecting the latter tive” immune systems. Activation of TLRs from fungal infections.1 Since 1997, 11 triggers nonspecific immune responses in members of the mammalian homologue of monocytes and macrophages. In addi- the Drosophila Toll receptor family have tion, TLRs are also found on immature been described.2 dendritic cells (DCs) and are capable of Structurally, TLRs consist of a leucine- triggering their maturation. In this man- rich repeat in the extracellular domain and ner, DCs matured through TLR activa- a Toll–interleukin 1 (IL-1) receptor ho- tion stimulate specific or adaptive im- mologous region3 (TIR domain) in their mune responses. intracellular portion. TLR4 (the so- In this article, we review recent data that called endotoxin receptor) recognizes li- link various surgical diseases to TLR path- popolysaccharide (LPS) present in the cell ways. We searched the MEDLINE data- Author Affiliations: wall of gram-negative bacteria and also en- base for the period 1966 to 2005 without Department of Surgery, Cork dogenous ligands such as heat shock pro- language restriction. Original or review ar- University Hospital, National teins (HSPs) 60 and 70. TLR2 is respon- ticles that described experimental data University of Ireland, Cork (Drs Romics, Coffey, Wang, and sible for the recognition of peptidoglycans published in original papers or summa- Redmond); and Department of (PGN), lipoteichoic acid (LTA), and bac- rized in review papers on the activation of Medicine, University of terial lipoprotein (BLP), as well as zymo- TLR signaling pathways in surgically rel- Massachusetts Medical School, san from fungi. TLR3 recognizes double- evant diseases were selected for inclu- Worcester (Dr Szabo). stranded RNA (dsRNA) from viruses. sion in this review. (REPRINTED) ARCH SURG/ VOL 141, JUNE 2006 WWW.ARCHSURG.COM 595 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 TLR3, 5, TLR1 and 6 TLR2 MD-2 TLR4 TLR2 and 4 PGN LPS dsRNA 7, and 9 Polymorphism MD-2 CD14 TLR TLR TLR 2 4 3 Cytoplasm TIRAP TIRAP Crohn Disease Sepsis Sepsis Sepsis Ulcerative Colitis Atherosclerosis SIRS Atherosclerosis Enteritis CAD Ulcerative Colitis Transplantation Immunotherapy Immunotherapy Crohn Disease MyD88 TRIF Wound Healing Wound Healing Atherosclerosis CAD Cytoplasm Sepsis Immunotherapy IRAK Tollip ? Experimental Colitis Wound Healing Transplantation Helicobacter pylori Infection Cell Necrosis TRAF6 ? AMI Helicobacter pylori Infection Sepsis MAPK NF-κB IRF-3 MyD88 Atherosclerosis Activation of TLR2/4 Immunotherapy Transcription IRAK Transplantation Nucleus Nucleus Pyogenic Infections DNADNA DNA Figure 2. Surgically relevant Toll-like receptor (TLR) pathways and their associations with various surgical diseases. AMI indicates acute myocardial Figure 1. Toll-like receptor (TLR) 2, TLR3, and TLR4 signaling pathways. infarction; CAD, coronary artery disease; IRAK, interleukin 1 Deficiency both in myeloid differentiation factor 88 (MyD88) and receptor–associated kinase; MyD88, myeloid differentiation factor 88; and Toll-interleukin 1 (IL-1) receptor domain-containing adaptor-inducing SIRS, systemic inflammatory response syndrome. interferon ␤ (TRIF) results in complete loss of nuclear factor ␬B (NF-␬B) activation, a factor that has a central role in inflammatory cytokine production. dsRNA indicates double-stranded RNA; IRAK, IL-1 Activated MyD88 recruits a death domain–containing receptor–associated kinase; IRF-3, interferon regulatory factor 3; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; serine–threonine kinase, the IL-1 receptor–associated ki- PGN, peptidoglycans; TIRAP, Toll-IL-1 receptor domain–containing adaptor nase (IRAK) (Figure 1). The IRAK family consists of IRAK-1, protein; Tollip, Toll-interacting protein; and TRAF6, tumor necrosis factor -2, -4, and -M isoforms. Notably, IRAK-4–deficient mice receptor–associated factor 6. are unresponsive to LPS-induced proinflammatory stimu- lation,11 whereas IRAK-1–deficient mice exhibit a partial THE SIGNALING PATHWAYS OF TLRs attenuation in LPS-induced inflammatory responses. Phos- phorylated IRAK associates with tumor necrosis factor To better understand the functions of the TLRs, their as- (TNF) receptor–associated factor 6 (TRAF6), which leads sociated signaling pathways should first be described to the activation of NF-␬B and mitogen-activated protein (Figure 1). TLR4 is the most widely studied TLR. Af- kinase (MAPK) (Figure 1). ter LPS ligation, TLR4 forms stable clusters (recepto- A central role has been attributed to TIR domain– somes) that recruit the adaptor molecule, MD-24 containing adaptor proteins (TIRAPs): TIRAP/MyD88- (Figure 1). MD-2–deficient mice are resistant to LPS- adaptor–like (Mal)12,13 and Toll/IL-1 receptor domain- induced shock, as are TLR4-mutant and TLR4-deficient containing adaptor-inducing interferon ␤ (TRIF) (Figure 1). mice.5 During gram-negative septic shock, circulating LPS This suggestion is based on the finding that a dominant is bound by LPS-binding protein (LBP) in the serum. This negative form of TIRAP/Mal prevents TLR4- but not TLR9- complex is subsequently recognized by CD14, which fa- mediated NF-␬B activation. Yamamoto et al14 showed that cilitates LPS-induced signaling.6 MD-2 either resides in mice deficient in both MyD88 and TRIF exhibit a com- a complex with TLR4 or is secreted in the serum when plete loss of TLR4-mediated NF-␬B activation. These data in excess.7 Having ligated with TLR4 at the cell surface, indicate that LPS-triggered NF-␬B activation involves either LPS is internalized rapidly via an unknown mechanism. MyD88 or TRIF. These molecules may represent future TLR activation induces either a core TLR response or therapeutic targets in the regulation of TLR-mediated a specific cellular response via the induction of different signaling. signaling pathways. As part of the core signaling path- way, myeloid differentiation factor 88 (MyD88) plays a TLRs IN SEPSIS AND THE SYSTEMIC central role (Figure 1). MyD88 interacts with TLRs via INFLAMMATORY RESPONSE SYNDROME their TIR domain. MyD88-deficient mice are unrespon- sive to LPS,8 and MyD88-deficient macrophages do not Figure 2 summarizes surgical diseases that are cur- respond to PGN and lipoproteins (TLR2 ligand) or rently associated with TLR pathways. Much of the evi- CpG DNA (TLR9 ligand). On the other hand, MyD88- dence that supports a role for TLR-mediated signaling deficient mice are highly susceptible to Staphylococcus in sepsis stems from murine studies. TLR4 activation is aureus infection.9 MyD88 deficiency modulates the now known to occur during the systemic inflammatory kinetics of the LPS-induced inflammatory response. The response syndrome (SIRS). The development of SIRS, af- activation of nuclear regulatory factor ␬B (NF-␬B) ter the administration of soluble heparan sulfate or elas- and c-Jun N-terminal kinases is delayed.10 Given the cen- tase, is TLR4 dependent. In keeping with this observa- tral role of this molecule in LPS-mediated signal trans- tion, Johnson et al15 demonstrated that exogenous duction, it represents a potential focal point for future macromolecules acting on TLRs can initiate a process that therapies. culminates in SIRS. (REPRINTED) ARCH SURG/ VOL 141, JUNE 2006 WWW.ARCHSURG.COM 596 ©2006 American Medical Association. All rights
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