TRP Channels as Sensors of Bacterial Endotoxins

Abstract

The cellular and systemic effects induced by bacterial lipopolysaccharides (LPS) have been solely attributed to the activation of the Toll-like receptor 4 (TLR4) signalling cascade. However, recent studies have shown that LPS activates several members of the Transient Receptor Potential (TRP) family of cation channels. Indeed, LPS induces activation of the broadly-tuned chemosensor TRPA1 in sensory neurons in a TLR4-independent manner, and genetic ablation of this channel reduced mouse pain and inflammatory responses triggered by LPS and the gustatory-mediated avoidance to LPS in fruit flies. LPS was also shown to activate TRPV4 channels in airway epithelial cells, an effect leading to an immediate production of bactericidal nitric oxide and to an increase in ciliary beat frequency. In this review, we discuss the role of TRP channels as sensors of bacterial endotoxins, and therefore, as crucial players in the timely detection of invading gram-negative bacteria.

Keywords: LPS; TRPA1; TRPV4; epithelial cells; sensory neurons.

Figure 1

Schematic representation of Transient Receptor Potential (TRP) ion channel structure. The six-transmembrane segment topology of the monomer (left) and tetrameric functional unit of TRP channels (right). The cytoplasmic NH₂- and COOH-terminal domains, and the transmembrane domain constituting the pore region are indicated. The transmembrane domain comprises segments 1–4 (green) distal to the pore and the segments 5 and 6 (dark green) proximal to the pore of the channel.

Figure 2

Effects of the activation of TRP channels in sensory neurons by lipopolysaccharides (LPS). LPS triggers activation the sensory nervous system by activation of TRPA1, TRPV1 and/or TRPM3 located at peripheral nerve terminals. TRPM8 activation by LPS occurs at cold temperatures. Sensory nerve activation leads to action potential generation and pain, and the local release of neuropeptides leading to neurogenic inflammation. CGRP, calcitonin gene-related peptide; SP, substance P.

Figure 3

Acute responses in epithelial cells after activation of TRPV4 by LPS. LPS shed by gram-negative bacteria during colonization near the epithelial surface activates TRPV4 channels expressed in ciliated epithelial cells, leading to a Ca²⁺ influx that triggers acute cellular responses such as the production of bactericidal nitric oxide and increased ciliary beat frequency. NO, nitric oxide; CBF, ciliary beat frequency.