ReviewVagal immune-to-brain communication: a visceral chemosensory pathway
Introduction
The brain is an important player in host defense against infection. In addition to coordinating metabolic, endocrine and behavioral changes that support the immune response, the brain modulates the immune system via neuroendocrine and direct neural regulation of immune cell functioning. But first, the immune system must alert the brain to the presence of an infection. This requirement implies the existence of an immunosensory system (Besedovsky and del Rey, 1992), in which immune-derived cells detect infections and signal the appropriate neural substrates. In this way, immune-nervous system interactions are characterized by bi-directional communication, aimed at the achievement of precise and effective host defense.
Immunosensory mechanisms can be classified into two general types of pathways: via specialized cells residing in brain barrier regions such as cerebrovascular endothelium (Van Dam et al., 1992, Ericsson et al., 1997) or choroid plexus (Herkenham et al., 1998) and circumventricular organs (Saper and Breder, 1994), or via peripheral sensory nerves associated with the vagus (Watkins et al., 1995a, Watkins et al., 1995b). Collectively, these ‘immune-to-brain mechanisms’ function as an immune chemosensory system organized to detect both pathogen and immune cell generated chemical stimuli.
Chemosensory systems, like other sensory systems, detect a wide range of stimuli, to which they must respond by rapidly activating the appropriate behavioral and physiological responses. For example, detection of olfactory stimuli associated with a predator requires behavioral responses such as hiding or escape, as well as endocrine and metabolic support for responses (e.g. stress hormones and glucose mobilization). In a similar way, immune chemosensory systems involve detection of a pathogen, followed by the induction of behavioral responses such as social isolation and reduced food intake. Concomitantly, physiological responses such as fever, increased sleep, and the mobilization of energy substrates support the peripheral immune responses. These responses are collectively referred to as ‘sickness symptoms’ or as the ‘acute phase’ of host defense.
Theoretically, any peripheral nerve may be capable of immunosensation. For instance, trigeminal ganglion cells respond to cytokines (Kobierski et al., 2000) which are immune-derived hormone-like mediators, and spinal visceral nerves respond to inflammation. However, the concept of immunosensation implies that responses to, for instance, cytokines lead to the initiation of brain-mediated acute phase responses, such as fever. Of peripheral nerves that have been investigated so far (which haven’t been many), support exists only for the vagus as an immunosensory nerve. Sectioning of the abdominal vagus nerve inhibits acute phase responses such as fever in some experimental paradigms (Watkins et al., 1995a, Watkins et al., 1995b, Sehic and Blatteis, 1996, Romanovsky et al., 1997, Fleshner et al., 1998). Concordantly, immune stimuli activate vagal sensory neurons (Niijima, 1996, Ek et al., 1998, Gaykema et al., 1998, Goehler et al., 1998a, Goehler et al., 1998b). Based on anatomical and functional considerations, the vagus nerve is particularly well suited for an immunosensory function. This nerve conveys a variety of chemosensory signals, such as signals arising from meal-related stimuli. The broad distribution of vagal afferents to most visceral structures, including those most frequently in contact with pathogens, such as the lung and gastrointestinal tract, ensures that vagal afferents are ideally positioned to detect immune activation early on in an infection. This review focuses on immune-activated vagal pathways, but because the existence of parallel pathways is a hallmark of sensory system organization (Ulinski, 1984) the importance of other immunosensory pathways (e.g. brain barrier cells) must also be recognized. It is not within the scope of this paper to include all relevant contributions to the field, but rather to provide sufficient information to convey the general structure and function of this novel chemosensory system.
Section snippets
Immune chemosensory mechanisms
Immune cells are capable of detecting dangerous micro-organisms and distinguishing them from benign and beneficial ones (Matzinger, 1994). The effectiveness of immune responses relies upon vigilant chemosensory surveillance rapidly responding to replicating bacteria and viruses. Two rather different mechanisms operate that lead to the activation of acute phase responses.
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T-cell independent. Specific pathogen products can bind to receptors expressed on the plasma membranes of certain immune cells
How do immune receptor cells signal the vagus?
Upon detection of pathogens, immune receptor cells release a variety of chemical substances capable of activating the nervous system. Important mediators include cytokines such as interleukin-1 (IL-1), tumour necrosis factor (TNF), interleukin-6 (IL-6) and interferon-gamma (IFN). Other likely mediators include prostaglandins, which are ubiquitous inflammatory mediators implicated in local inflammatory processes, and notably, in the initiation of brain mediated host defense responses, especially
Primary afferent activation
Like other chemosensory pathways, vagal immunosensation involves the activation of primary afferent neurons as the initial stimulus-to-nervous system interface. Primary afferent neurons associated with the vagus nerve reside in a fused ganglion complex: the vagal–glossopharyngeal ganglion, which consists of the nodose (inferior vagal), the petrosal (glossopharyngeal) and jugular (superior vagal) ganglia. Both pathogen-derived chemical constituents and immune cell-derived cytokines have been
Ascending immunosensitive pathways
Bacteria-derived immune stimuli including LPS and SEB, as well as cytokines including IL-1, activate interconnected nuclei in the brainstem, midbrain and forebrain that also relay and process both gustatory and other visceral sensory information (Wan et al., 1994, Day and Akil, 1996, Elmquist et al., 1996). From studies assessing c-Fos expression and separate studies employing neuronal tract tracing techniques, it is possible to tentatively identify three parallel pathways conveying
Perspectives: organizing features of immunosensory systems
From the foregoing, it is evident that vagal viscerosensory neurons respond to immune-related stimuli, and that this information is processed via a similar, but ultimately unique, pattern of neural activation as other chemosensory systems. Immune cells respond to variety of pathogen-associated chemicals by releasing mediators, such as cytokines that further activate immunosensory pathways serving to generate appropriate responses to the stimulus (i.e. acute phase responses). A pictorial
Acknowledgments
This work was supported by NIH grants MH555283, MH01558, MH00314, and NIH grant DC 00147 to T.E. Finger of the University of Colorado Health Science Center.
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