The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

TY - JOUR

T1 - The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

AU - Hovland, Anders

AU - Jonasson, Lena

AU - Garred, Peter

AU - Yndestad, Arne

AU - Aukrust, Pål

AU - Lappegård, Knut T

AU - Espevik, Terje

AU - Mollnes, Tom E

N1 - Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis.

AB - Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis.

KW - Animals

KW - Atherosclerosis

KW - Cholesterol, LDL

KW - Complement C3a

KW - Complement C5a

KW - Complement System Proteins

KW - Disease Models, Animal

KW - Humans

KW - Immune System

KW - Immunity, Innate

KW - Inflammation

KW - Inflammation Mediators

KW - Mice

KW - Signal Transduction

KW - Toll-Like Receptors

U2 - 10.1016/j.atherosclerosis.2015.05.038

DO - 10.1016/j.atherosclerosis.2015.05.038

M3 - Review

C2 - 26086357

SN - 0021-9150

VL - 241

SP - 480

EP - 494

JO - Atherosclerosis

JF - Atherosclerosis

IS - 2

ER -