The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.

Lipopolysaccharides (LPS), the major components of the wall of gram-negative bacteria, trigger powerful defensive responses in the airways via mechanisms thought to rely solely on the Toll-like receptor 4 (TLR4) immune pathway. Here we show that airway epithelial cells display an increase in intracellular Ca2+ concentration within seconds of LPS application. This response occurs in a TLR4-independent manner, via activation of the transient receptor potential vanilloid 4 cation channel (TRPV4). We found that TRPV4 mediates immediate LPS-induced increases in ciliary beat frequency and the production of bactericidal nitric oxide. Upon LPS challenge TRPV4-deficient mice display exacerbated ventilatory changes and recruitment of polymorphonuclear leukocytes into the airways. We conclude that LPS-induced activation of TRPV4 triggers signaling mechanisms that operate faster and independently from the canonical TLR4 immune pathway, leading to immediate protective responses such as direct antimicrobial action, increase in airway clearance, and the regulation of the inflammatory innate immune reaction.

The non-selective cation channel TRPA1 is best known as a broadly-tuned sensor expressed in nociceptive neurons, where it plays key functions in chemo-, thermo-, and mechano-sensing. However, in this review we illustrate how this channel is expressed also in cells of the immune system. TRPA1 has been detected, mainly with biochemical techniques, in eosinophils, mast cells, macrophages, dendritic cells, T cells, and B cells, but not in neutrophils. Functional measurements, in contrast, remain very scarce. No studies have been reported in basophils and NK cells. TRPA1 in immune cells has been linked to arthritis (neutrophils), anaphylaxis and atopic dermatitis (mast cells), atherosclerosis, renal injury, cardiac hypertrophy and inflammatory bowel disease (macrophages), and colitis (T cells). The contribution of TRPA1 to immunity is dual: as detector of cell stress, tissue injury, and exogenous noxious stimuli it leads to defensive responses, but in conditions of aberrant regulation it contributes to the exacerbation of inflammatory conditions. Future studies should aim at characterizing the functional properties of TRPA1 in immune cells, an essential step in understanding its roles in inflammation and its potential as therapeutic target.

No abstract