Endotoxin, TLR4 Signaling and Vascular Inflammation: Potential Therapeutic Targets in Cardiovascular Disease

Abstract

Cardiovascular disease ranks among the leading causes of morbidity and mortality in adult populations in the Western world. Significant progress in understanding the etiology of cardiovascular disease has come from recent recognition that chronic inflammation plays a key role in its development. The principal mediators of this inflammatory response, and the mechanisms by which they work, however, are incompletely understood. Moreover, the complex nature of the inflammatory response poses significant challenges to the development of effective and targeted treatments. Potentially promising targets to reduce inflammation in atherosclerosis include Toll-like receptor (TLR) pathways and anti-inflammatory factors that modulate TLR signaling. In this review, we outline studies that provide insight into the links between cardiovascular disease and inflammation, focusing on innate immunity and endotoxin/TLR4 signaling. We also discuss the contribution of specific host immune/inflammatory responses to atherogenesis, and describe cellular signaling pathways (lipopolysaccharide-binding protein [LBP], CD14, MD-2, TLR4, MyD88, and NF-kappaB, among others) that play key roles in innate immune signaling. Finally, we discuss the therapeutic potential of modulating these cellular signaling pathways as future strategies for the prevention and treatment of cardiovascular disease, including such approaches as specific targeting of the TLR4 signaling pathway, antibiotic therapy, drug classes with broad anti-inflammatory activity (statins, thiazolidinediones), and the potential of vaccine development. Because of the complexity of the links between low-level chronic infections, inflammation, and atherosclerosis, treatment and prevention of cardiovascular disease will likely require an integrated approach that utilizes a combination of these strategies to target the underlying inflammatory processes.

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…Interestingly, individuals with lifestyles that involve smoking and drinking (risk factors for cardiovascular disease) have increased levels of endotoxin in their circulation (Cani et al, 2008;Manco et al, 2010;Sun et al, 2010). Furthermore, low circulating levels of endotoxin may lead to enhanced pathogenesis of atherosclerosis (Stoll et al, 2004(Stoll et al, , 2006). An interesting question includes mechanisms by which TLRs mediate the interaction between innate immune memory and dysfunction of cardiovascular tissues.…”

GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway

“…The activation of macrophages resulting from the interaction of the bacterial cell wall component lipopolysaccharide (LPS) with Toll-like receptor 4 (TLR4) constitutes a major pathway for the initiation of innate immune responses and the development of inflammation. In macrophages, activation of TLR4 by LPS has been shown to recruit downstream signalling proteins and induce the generation of reactive oxygen species (ROS) and proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and TNFα (Doyle and O'Neill, 2006;Gill et al, 2010;Stoll et al, 2006;Zhang and Ghosh, 2001;Zhou et al, 2010). In addition to their bactericidal activity, their signalling role and their impact on the expression of pro-inflammatory cytokines, the ROS generated by the TLR4 pathway have also been shown to cause tissue damage and are central to the progression and pathology of many inflammatory diseases (Gill et al, 2010).…”

Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal

“…TLR4 is crucial for effective host cell responses to LPS from Gram-negative bacteria (21,22). Upon LPS binding, TLR4 oligomerizes and recruits adaptors to its intracellular TIR domains, triggering downstream signaling (23).…”