Roles of Neuronal TRP Channels in Neuroimmune Interactions

In: Neurobiology of TRP Channels. Boca Raton (FL): CRC Press/Taylor & Francis; 2017. Chapter 15.


In order to survive, organisms must adapt to environmental conditions that may subject them to changes in physical variables such as temperature, pressure, light, concentration of chemicals, and so on. In addition, they must be able to react appropriately to their biological milieu and especially to the challenge presented by pathogens that colonize tissues, producing injury, depletion of resources, and interference with vital metabolic functions. The adaptation processes typically entail the initial detection of external stimuli and the posterior implementation of reflex reactions. While in the classical view the sensing of physical stimuli is carried out mainly by sensory neurons and the detection of pathogen-derived cues by the immune cells, in recent years it has become clear that there is a functional interplay between the nervous and immune systems. These neuroimmune interactions arise not only from an intense biochemical cross-talk between neurons and immune cells, but also from the overlap in the sensory functions of these cells.

As exciting and important as it is, the study of neuroimmune interactions seems to be in its infancy, mainly due to insufficient interaction between immunologists and neuroscientists. There is, however, one concept—inflammation—that serves as a meeting point for these research communities. But again it is interesting to see that for immunologists, inflammation is mainly related to the action and regulation of immune cells, without much consideration given to neural functions. For neuroscientists, and especially for sensory neuroscientists, inflammation is mostly associated with “neurogenic inflammation.” This concept refers to the consequences of the local release of inflammatory mediators upon activation of sensory nerve endings, which include vasodilation, plasma extravasation, but also recruitment of leukocytes and degranulation of mast cells (Chiu et al., 2012; Engel et al., 2011a; Fernandes et al., 2009; Geppetti et al., 2008; Russell et al., 2014).

Neuroimmune interactions can take place at systemic levels, as occurs when acetylcholine is released to the circulation by the parasympathetic innervation thus influencing the function of distal immune cells, but also at the level of close-range cross-talks between nerve and immune cells (Andersson and Tracey, 2012; Chiu et al., 2012; Ordovas-Montanes et al., 2015). Neuronal signals such as neurotransmitters and neuropeptides influence hematopoiesis, priming and migration of immune cells, while cytokines and histamine produced by the latter can lead to neuronal activation and sensitization. In the central nervous system, the two-sided interplay between neurons and immune cells is particularly evident for microglia and mast cells, which have important roles in neuroinflammatory conditions (Skaper et al., 2014).

Several advances in the field of neuroimmunology have been driven by the need of considering, and in some cases reconsidering, the function of the nervous system to understand pathologies that were mostly defined as immune disorders (see, e.g., Bautista et al., 2014; Belvisi et al., 2016; Halliez and Buret, 2015; Hyland et al., 2014; Ji, 2015; Mayer et al., 2015; Mazzone and Undem, 2016; O'Malley, 2015; Undem and Taylor-Clark, 2014). Increasing evidence indicates that neuroimmune interactions are implicated in hypersensitivity and hyperreactivity conditions such as irritable bowel syndrome, rhinitis, and asthma. Additional momentum has been gained through the recent identification of some of the molecules and receptors implicated in the mechanisms of cellular neuroimmune cross-talk.

In this chapter, we focus on transient receptor potential (TRP) proteins (Flockerzi and Nilius, 2014; Nilius and Flockerzi, 2014), which compose a superfamily of cation channels that play increasingly acknowledged roles in the pathophysiology of all of the vertebrate systems, including the nervous (Gerhold and Bautista, 2009; Julius, 2013; Mickle et al., 2015; Talavera et al., 2008; Vennekens et al., 2012) and immune (Parenti et al., 2016) systems. They are implicated in inflammatory responses, not only through the phenomenon of neurogenic inflammation (Geppetti et al., 2008; Xanthos and Sandkuhler, 2014), but also via their function in proinflammatory immune cells either resident in the nervous tissues or infiltrating, such as microglia (Echeverry et al., 2016; Eder, 2010; Sharma and Ping, 2014), macrophages (Isami et al., 2013), neutrophils (Gelderblom et al., 2014), and mast cells (Freichel et al., 2012). The two main protagonists are the capsaicin receptor TRPV1 and the broadly tuned noxious chemosensor TRPA1. The functional expression of these channels in nociceptive neurons and their roles in neurogenic inflammation are clearly established (Bevan et al., 2014; Nilius et al., 2012; Zygmunt and Hogestatt, 2014). In the following, we discuss how several neuronal TRP channels may serve to sense exogenous pathogen-derived cues, as well as endogenous effector molecules released by immune cells, and review the implication of these channels in neuroimmune interactions during inflammatory processes.

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