TRPA1: A gatekeeper for inflammation

Abstract

Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract.

Figure 1

Mechanisms of neurogenic inflammation. (Left) TRPA1 is expressed by sensory afferents that have cell bodies in the vagus nerve (blue), trigeminal ganglia ( green), and dorsal root ganglia (red ). These afferents innervate peripheral targets, including the skin, the airways, and the GI tract. (Right) TRPA1 activation is required for the release of neuropeptides such as substance P, calcitonin gene-related peptide (CGRP), and neurokinin A (NKA), which promote and modulate inflammatory responses.

Figure 2

Diverse mechanisms of TRPA1 activation. Endogenous and exogenous agonists covalently modify cysteines ( yellow; C) in the TRPA1 N terminus to promote channel activity. In addition, signaling molecules downstream of G protein–coupled receptors (GPCRs) regulate TRPA1 channel activity. Other putative binding/modulatory sites that regulate channel activity include ankyrin domains ( gray), calcium-binding domains (red; D), the familial episodic pain syndrome (FEPS) mutation ( green; N), and zinc-binding sites (orange; C, H). Additional TRPA1 domains for activation by phospholipase C (PLC) and Gβγ are not known.

Figure 3

TRPA1 in airway inflammation. The respiratory system is densely innervated by TRPA1-expressing primary afferent fibers from the trigeminal nerve, vagus nerve, and dorsal root ganglia. TRPA1 is activated by numerous exogenous irritants and endogenous mediators of airway inflammation. TRPA1 activation in the airways has been linked to cough, asthma, chronic obstructive pulmonary disease (COPD), bronchospasm, and mucus secretion.

Figure 4

TRPA1-expressing sensory nerves innervate the colon and mediate neuropeptide release in response to TRPA1 activators such as 4-hydroxynonenal (4-HNE). Experimental colitis models induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulfate (DSS) lead to hypersensitivity to colorectal distension (CRD) and pain.