A nervous S1P of the lung: activation of airway nerves by sphingosine‐1‐phosphate

Sphingosine-1-phosphate (S1P) is a bioactive lipid, generated from sphingosine by sphingosine kinases, that regulates both vascular and immune function. As such, S1P has attracted attention as an important regulator of inflammatory diseases. The classic signs of inflammation such as calor (heat), rubor (redness) and tumour (swelling) are immediately recognizable as the result of changes in vascular patency and permeability. Another classic sign of inflammation, dolor or pain, suggests a role for sensory nerves. In this issue of The Journal of Physiology, Patil et al. (2019) report that S1P has a profound impact on a subset of sensory nerves that act as sentinels for the protection of the airways. These sensory nerves project peripherally from the vagal ganglia (cranial nerve X) to the lower airways and their activation, caused by noxious stimuli such as capsaicin (the pungent agent in chili), elicits an array of defensive responses. Thus these ‘nociceptive’ sensory nerves regulate central breathing networks (evoking cough, apnoea) and parasympathetic nerves innervating bronchial smooth muscle and airway mucosal gland function, evoking bronchospasm and hypersecretion, respectively. In some cases, activated nociceptive nerves release neuropeptides, such as substance P, from their peripheral terminals, which can increase vascular permeability and bronchospasm and activate immune cells such as mast cells – thus potentiating the inflammatory state. Inflammation activates nociceptive nerves to trigger unpleasant sensations and debilitating reflexes. Nevertheless, only a few receptors for specific inflammatory mediators (e.g. bradykinin B2 receptor) are known to be expressed on vagal nociceptive nerves. The Undem group had previously used an unbiased RNA-sequencing approach to identify vagal nociceptor inflammatory receptors (Wang et al. 2017), and this led to their identification of sphingolipid receptors. S1P has five cognate G-protein-coupled receptors (S1PR1–S1PR5), although S1P may also signal via intracellular targets. Patil et al. (2019) used single-neuron RT-PCR to show that all vagal nociceptive neurons express S1PR3, whereas S1PR1 and S1PR2 were expressed by less than 1/3 of the nociceptive population and S1PR4 and S1PR5 were absent. Furthermore, they showed that exogenously applied S1P activated vagal nociceptors innervating an ex vivo lung preparation using two separate methods: detection of single fibre action potential discharges using an extracellular recording electrode placed in the vagal ganglia; and two-photon imaging of calcium transients in vagal airway neurons using the reporter gCamp6s, selectively expressed under the control of afferent-specific cre recombinase. Although the latter technique is less informative than the former electrophysiological method with respect to details of number and pattern of action potential discharge, it provides the enormous advantage of being able to evaluate thousands of neurons in a single experiment. The S1P-induced nociceptor activation was inhibited by TY 52156, a partially selective S1PR3 antagonist, suggesting a role for S1PR3. However, the role S1P and its receptors in inflammatory disease in general is complicated by a paucity of selective ligands. Nevertheless, the importance of S1PR3 was further established by the observation by Patil et al. (2019) that S1P failed to activate vagal airway nociceptors in S1PR3−/− mice. These data indicate that S1P (via S1PR3) is a potent stimulator of airway nociceptors, and is consistent with reports that neuronally mediated airway hyper-reactivity in a mouse model of asthma is potentiated by FTY720, a prodrug of a partially selective S1PR3 agonist (Trankner et al. 2014). It is likely that vagal nociceptors innervating other visceral organs will also be activated by S1P. S1P has also been shown to activate somatosensory nociceptors in the skin via S1PR3 (Camprubi-Robles et al. 2013; Hill et al. 2018). The intracellular signalling that links S1PR3 activation with airway nociceptor depolarization is presently unknown, although Patil et al. (2019) have ruled out signalling via the nociceptive transient receptor potential channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1). This observation is inconsistent with some somatosensory nociceptor studies (Hill et al. 2018), and these differences in signalling mimics reports of S1P receptors coupling with different Gα proteins in different innate immunity cell types. S1P activates both proinflammatory and anti-inflammatory pathways, and the balance between these pathways depends on the S1P concentration and the receptors and cell types involved. Patil et al. (2019) have shown that exogenously applied S1P can activate airway nociceptive nerves. The next step is to determine whether endogenously synthesized S1P activates these nerves in a meaningful manner in airway disease. S1P has been implicated in a host of lung diseases ranging from asthma to acute lung injury, but S1P ligands have not yet made it to the clinic, perhaps due to the complexity of S1P signalling. Nevertheless, Patil et al. (2019) have shown that S1P evokes more action potentials in airway nociceptors than the irritant capsaicin (TRPV1 agonist) and such efficacy may well indicate a significant role for S1P in endogenous inflammation nociceptor signalling.