Toll-like Receptor 4 Modulation as a Strategy to Treat Sepsis

Abstract

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock.

Modulation of Macrophage Cell Death, Pyroptosis by Host Defense Peptide LL-37

“…As a therapeutic strategy, the blocking of LPS action (e.g. TLR4 KO) protects mice from systemic inflammation and tissue damage in endotoxemia 34) , and the blocking of ATP action (e. g. administration of a P2X7 antagonist) improve the survival rate in E. coliinduced sepsis 35) . Thus, the present findings indicate that LL-37 can be a promising candidate for sepsis because it has potent biological functions, including the inhibition of pyroptosis, modulation of inflammatory cytokine production and antimicrobial activity (Figure-5).…”

The role of protein–protein interactions in Toll-like receptor function

“…Only small amounts of LPS are required to stimulate the TLR4 pathway and hence alert the immune system to invading pathogens, and overstimulation of this pathway can lead to sepsis. Septic shock remains the primary killer in intensive care units, with a 30% mortality rate, and millions of deaths worldwide every year [6][7][8]. Identifying drugs that inhibit TLR4 complex dimerization and hence sepsis is thus of great interest.…”

“…In 1997 Janeway further identified the family of PRRs called the Toll-like receptors (TLRs) [4], which remain the most extensively studied PRRs today. The importance of TLRs is highlighted by the various infectious and noninfectious disease states that can result from their dysregulation, and by their consequent extensive therapeutic targeting [5][6][7][8][9].…”

Alternative Therapies for Septic Shock: Beyond Early Goal-Directed Therapy

“…Of particular interest in sepsis are TLR2 and TLR4 because expression of these PRRs is increased on monocytes in healthy volunteers undergoing an LPS challenge (Wittbole et al, 2005), and in patients with sepsis (Harter et al, 2004). TLR4 binds with MD2, an extracellular accessory protein, which form a complex that interacts with LPS ( Figure 4) (Wittebole, et al, 2010). Eritoran is a LPS antagonist that binds to the TLR4-MD-2 complex, rendering it unable to illicit the immune response.…”

“…Resatorvid is another agent that inhibits TLR4 signaling by binding directly to a specific amino acid in the TLR4-intracellular domain, thus is a TRL4 antagonist (Wittebole, et al, 2010).…”