Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2

TLDR

Sepsis complications arise from both Gram‑negative and Gram‑positive bacterial infections, and lipopolysaccharide has been shown to activate cells through Toll‑like receptor 2. This study examines how soluble peptidoglycan and lipoteichoic acid from Gram‑positive bacteria trigger cellular activation. Soluble peptidoglycan and lipoteichoic acid bind the CD14 co‑receptor and stimulate NF‑κB activation in host cells, mirroring the LPS pathway. In HEK293 cells expressing TLR2, but not TLR1 or TLR4, soluble peptidoglycan and lipoteichoic acid activate NF‑κB, a response that is CD14‑dependent, serum‑independent, and resistant to polymyxin B, confirming TLR2 as a transducer for these Gram‑positive components.

Abstract

The life-threatening complications of sepsis in humans are elicited by infection with Gram-negative as well as Gram-positive bacteria. Recently, lipopolysaccharide (LPS), a major biologically active agent of Gram-negative bacteria, was shown to mediate cellular activation by a member of the human Toll-like receptor family, Toll-like receptor (TLR) 2. Here we investigate the mechanism of cellular activation by soluble peptidoglycan (sPGN) and lipoteichoic acid (LTA), main stimulatory components of Gram-positive bacteria. Like LPS, sPGN and LTA bind to the glycosylphosphatidylinositol-anchored membrane protein CD14 and induce activation of the transcription factor NF-κB in host cells like macrophages. We show that whole Gram-positive bacteria, sPGN and LTA induce the activation of NF-κB in HEK293 cells expressing TLR2 but not in cells expressing TLR1 or TLR4. The sPGN- and LTA-induced NF-κB activation was not inhibited by polymyxin B, an antibiotic that binds and neutralizes LPS. Coexpression together with membrane CD14 enhances sPGN signal transmission through TLR2. In contrast to LPS signaling, activation of TLR2 by sPGN and LTA does not require serum. These findings identify TLR2 as a signal transducer for sPGN and LTA in addition to LPS.